BioMed Research International: Pulmonology The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Ginsenoside Rg1 Ameliorates Cigarette Smoke-Induced Airway Fibrosis by Suppressing the TGF-β1/Smad Pathway In Vivo and In Vitro Tue, 21 Mar 2017 09:27:10 +0000 Small airway fibrosis is a key pathological process accompanying chronic obstructive pulmonary disease (COPD) and includes fibroblast/myofibroblast transdifferentiation and excessive extracellular matrix deposition. Ginsenoside Rg1, one of the main active ingredients of Panax ginseng, has been shown to exert an antifibrotic effect in many tissues. However, little is known about the underlying mechanism and whether ginsenoside Rg1 can exert an effect on small airway fibrosis. We investigated the anti-small airway fibrosis effects of ginsenoside Rg1 in human embryonic lung fibroblasts and in COPD rats. We found that ginsenoside Rg1 effectively reduced the degree of pulmonary fibrosis, decreased the expression of α-smooth muscle actin, collagen I, and matrix metalloproteinase 9, and maintained the ratio of matrix metalloproteinase 9 to tissue inhibitor of metalloproteinase 1. Importantly, ginsenoside Rg1 significantly attenuated cigarette smoke extract-induced upregulation of transforming growth factor β1, TGF-β receptor I, phospho-Smad2, and phospho-Smad3. In addition, ginsenoside Rg1 mimicked the effect of SB525334, a TGF-β receptor I-Smad2/3 inhibitor. Collectively, these results suggest that ginsenoside Rg1 may suppress cigarette smoke-induced airway fibrosis in pulmonary fibroblasts and COPD rats by inhibiting the TGF-β1/Smad signaling pathway. Sibin Guan, Qian Liu, Fengfeng Han, Wen Gu, Lin Song, Yue Zhang, Xuejun Guo, and Weiguo Xu Copyright © 2017 Sibin Guan et al. All rights reserved. Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis Mon, 27 Feb 2017 06:12:56 +0000 Purpose. Radiation-induced lung fibrosis (RILF) is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX) has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored. Materials and Methods. We used micro-computed tomography (micro-CT) and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF. Results. Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI-) 1 and fibronectin (FN) and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA) phosphorylation but not TGF-β/Smad in both irradiated lung tissues and epithelial cells. Conclusions. Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms. Jong-Geol Lee, Sehwan Shim, Min-Jung Kim, Jae Kyung Myung, Won-Suk Jang, Chang-Hwan Bae, Sun-Joo Lee, Kyeong Min Kim, Young-Woo Jin, Seung-Sook Lee, and Sunhoo Park Copyright © 2017 Jong-Geol Lee et al. All rights reserved. The Influence of Age on Interaction between Breath-Holding Test and Single-Breath Carbon Dioxide Test Tue, 31 Jan 2017 13:42:48 +0000 Introduction. The aim of the study was to compare the breath-holding test and single-breath carbon dioxide test in evaluation of the peripheral chemoreflex sensitivity to carbon dioxide in healthy subjects of different age. Methods. The study involved 47 healthy volunteers between ages of 25 and 85 years. All participants were divided into 4 groups according to age: 25 to 44 years (), 45 to 60 years (), 60 to 75 years (), and older than 75 years (). Breath-holding test was performed in the morning before breakfast. The single-breath carbon dioxide (SB-CO2) test was performed the following day. Results. No correlation was found between age and duration of breath-holding () and between age and peripheral chemoreflex sensitivity to CO2 (). In all age groups there were no significant differences in the mean values from the breath-holding test and peripheral chemoreflex sensitivity tests. In all groups there was a strong significant inverse correlation between breath-holding test and SB-CO2 test. Conclusion. A breath-holding test reflects the sensitivity of the peripheral chemoreflex to carbon dioxide in healthy elderly humans. Increasing age alone does not alter the peripheral ventilatory response to hypercapnia. Nikita Trembach and Igor Zabolotskikh Copyright © 2017 Nikita Trembach and Igor Zabolotskikh. All rights reserved. Bronchoscopic Diagnosis and Treatment of Primary Tracheobronchial Amyloidosis: A Retrospective Analysis from China Thu, 19 Jan 2017 00:00:00 +0000 Objective. To assess the value of bronchoscopy in the diagnosis and treatment of primary tracheobronchial amyloidosis (TBA), in order to reduce misdiagnosis rates and improve prognosis. Methods. Clinical data of 107 patients with TBA reported from 1981 to 2015 in China were retrospectively analyzed for clinical features, bronchoscopic manifestations, pathologies, treatments, and outcomes. Results. 105 of 107 TBA patients were pathologically confirmed by bronchoscopy. Main bronchoscopic manifestations of TBA were single or multiple nodules and masses within tracheobronchial lumens; local or diffuse luminal stenosis and obstruction; luminal wall thickening and rigidity; rough or uneven inner luminal walls; congestion and edema of mucosa, which was friable and prone to bleeding upon touch; and so forth. 53 patients were treated with bronchoscopic interventions, like Nd-YAG laser, high-frequency electrotome cautery, freezing, resection, clamping, argon plasma coagulation (APC), microwaving, stent implantation, drug spraying, and other treatments. 51 patients improved, 1 patient worsened, and 1 died. Conclusion. Bronchoscopic biopsy is the primary means of diagnosing TBA. A variety of bronchoscopic interventions have good short-term effects on TBA. Bronchoscopy has important value in the diagnosis, severity assessment, treatment, efficacy evaluation, and prognosis of TBA. Xiaoxiao Lu, Bixiu He, Ge Wang, Baimei He, Lijing Wang, and Qiong Chen Copyright © 2017 Xiaoxiao Lu et al. All rights reserved. Impact of Chronic Obstructive Pulmonary Disease on Long-Term Outcome in Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention Wed, 30 Nov 2016 13:27:49 +0000 Objective. The aim of this study was to investigate the association between COPD and major adverse cardiovascular and cerebral events (MACCE) in patients undergoing percutaneous coronary intervention (PCI). Methods. 2,362 patients who underwent PCI were included in this study. Subjects were divided into 2 groups: with COPD () and without COPD ( = 2,129). Cox proportional hazards models were analyzed to determine the effect of COPD on the incidence of MACCE. Results. The patients with COPD were older () and were more likely to be current smokers () and have had hypertension () and diabetes mellitus (). Prevalence of serious cardiovascular comorbidity was higher in the patients with COPD, including a history of MI () and HF (). Compared with non-COPD group, the COPD group showed a higher risk of all-cause death (hazard ratio (HR): 2.45, ), cardiac death (HR: 2.53, ), MI (HR: 1.387, ), and HF (HR: 2.25, ). Conclusions. Patients with CAD and concomitant COPD are associated with a higher incidence of MACCE (all-cause death, cardiac death, MI, and HF) compared to patients without COPD. The patients with a history of COPD have higher in-hospital and long-term mortality rates than those without COPD after PCI. Ming Zhang, Yun-Jiu Cheng, Wei-ping Zheng, Guang-Hui Liu, Huai-Sheng Chen, Yu Ning, Xin Zhao, Li-Xiao Su, and Li-juan Liu Copyright © 2016 Ming Zhang et al. All rights reserved. Kinetics of Cardiac Output at the Onset of Exercise in Precapillary Pulmonary Hypertension Sun, 20 Nov 2016 08:38:21 +0000 Purpose. Cardiac output (CO) is a cornerstone parameter in precapillary pulmonary hypertension (PH). The Modelflow (MF) method offers a reliable noninvasive determination of its beat-by-beat changes. So MF allows exploration of CO adjustment with the best temporal resolution. Methods. Fifteen subjects (5 PH patients, 10 healthy controls) performed a submaximal supine exercise on a cycle ergometer after 5 min of rest. CO was continuously determined by MF (). Kinetics of heart rate (HR), stroke volume (SV), and CO were determined with 3 monoexponential models. Results. In PH patients, we observed a sudden and transitory drop of SV upon exercise onset. This implied a transitory drop of CO whose adjustment to a new steady state depended on HR increase. The kinetics of HR and CO for PH patients was slower than that of controls for all models and for SV in model 1. SV kinetics was faster for PH patients in models 2 and 3. Conclusion. This is the first description of beat-by-beat cardiovascular adjustments upon exercise onset in PH. The kinetics of HR and CO appeared slower than those of healthy controls and there was a transitory drop of CO upon exercise onset in PH due to a sudden drop of SV. Frédéric Lador, Aurélien Bringard, Samir Bengueddache, Guido Ferretti, Karim Bendjelid, Paola M. Soccal, Stéphane Noble, Maurice Beghetti, Denis Chemla, Philippe Hervé, and Olivier Sitbon Copyright © 2016 Frédéric Lador et al. All rights reserved. Genetic Polymorphism of Angiotensin-Converting Enzyme and Chronic Obstructive Pulmonary Disease Risk: An Updated Meta-Analysis Tue, 18 Oct 2016 07:12:54 +0000 The relationship between polymorphism of the angiotensin I converting enzyme (ACE) gene and chronic obstructive pulmonary disease (COPD) has been examined in many previous studies. However, their results were controversial. Therefore, we performed a meta-analysis to evaluate the relationship between the ACE gene and the risk of COPD. Fourteen case-control studies were included in this meta-analysis. The pooled value, odds ratio (OR), and 95% confidence interval (95% CI) were used to investigate the strength of the association. The meta-analysis was performed using comprehensive meta-analysis software. Our meta-analysis results revealed that ACE polymorphisms were not related to the risk of COPD ( in each model). In further analyses based on ethnicity, we observed an association between insertion/deletion polymorphism of the ACE gene and risk of COPD in the Asian population (codominant 2, OR = 3.126, 95% CI = 1.919–5.093, ; recessive, OR = 3.326, 95% CI = 2.190–5.050, ) but not in the Caucasian population ( in each model). In conclusion, the present meta-analysis indicated that the insertion/deletion polymorphism of the ACE gene may be associated with susceptibility to COPD in the Asian population but not in the Caucasian population. However, the results of the present meta-analysis need to be confirmed in a larger sample. Sang Wook Kang, Su Kang Kim, Joo-Ho Chung, Hee-Jae Jung, Kwan-Il Kim, Jinju Kim, and Ju Yeon Ban Copyright © 2016 Sang Wook Kang et al. All rights reserved. The Time Course of Pulmonary Function Tests in COPD Patients with Different Levels of Blood Eosinophils Sun, 16 Oct 2016 08:14:45 +0000 Only very few studies have investigated the influence of eosinophils on the functional progression of COPD. We aimed at retrospectively analyzing the trend of pulmonary function tests over time in patients with COPD according to two baseline blood eosinophil cell count strata (<2% [EOS−] and ≥2% [EOS+]). We used the last 9-year data present in the database of our outpatient clinic and selected only those who had two blood counts that would guarantee the stability of the value of eosinophils and serial spirometry for 4 consecutive years. The analysis of the time course of the spirometric variables analysed showed differences in FEV1 and FVC decline between the subjects of the EOS− group and those of the EOS+ group. The integrated evaluation of our results suggests that the different level of blood eosinophils in the two groups may have influenced independently the time course of the pulmonary function tests and identify two subgroups of subjects with specific disease characteristics: the hyperinflator and the rapid decliner, respectively. Paola Rogliani, Ermanno Puxeddu, Chiara Ciaprini, Josuel Ora, Angelo Onorato, Gabriella Pezzuto, Luigino Calzetta, and Mario Cazzola Copyright © 2016 Paola Rogliani et al. All rights reserved. Effect of Xinjiang Uyghur Vernonia anthelmintica Willd Injection Treatment with Silicosis Fibrosis Mon, 10 Oct 2016 07:38:10 +0000 Objective. To observe the curative effect of VAWI on Xinjiang Uygur patients with silicosis fibrosis. Methods. After we diagnosed the 40 patients with the first phase of silicosis, we randomly divided them into two groups: the basic treatment group (group A, ) and the VAWI group (group B, ). At the same time, we selected the age-matched healthy patients (). We applied the combined protein chip with SELDI-TOF-MS to carry out the serum analysis. The data were analyzed throughout data preprocessing, difference in PEAK screening, hierarchical cluster analysis, and Principal Component Analysis (PCA). We built decision tree model and predict the difference between the PEAK corresponding proteins. Results. The proteins peaks corresponding to name, predicted protein, and gene name were as follows: M2001_69, amyloid beta a4 protein, APP, and M2017_02, amyloid beta a4 protein, APP. The different expression of proteins in patients with silicosis was found before and after with VAWI treatment. The predicted proteins were as follows: M1982_50, amyloid beta a4 protein, APP; M3164_50, fibrinogen alpha chain frag, FGA; M3379_28, fibrinogen alpha chain frag, FGA; and so on. Conclusion. VAWI presented curative effect on patients with silicosis fibrosis via the alternation of proteins expression in serum. Guitao Liu, Yingjia Liu, Lu Jin, Cuidong Li, Liping Nie, Yanhua Wei, Wenyu Wang, Yuhong Xu, Nuziguli Nusilaiti, Ping Hua, Xiujuan Li, Xiaohua Wang, Wenlong Wei, and Hamulati Wufuer Copyright © 2016 Guitao Liu et al. All rights reserved. Effects of Bufei Yishen Granules Combined with Acupoint Sticking Therapy on Pulmonary Surfactant Proteins in Chronic Obstructive Pulmonary Disease Rats Tue, 06 Sep 2016 14:12:19 +0000 Our previous studies have demonstrated the beneficial effects of Bufei Yishen granules combined with acupoint sticking therapy (the integrated therapy) in chronic obstructive pulmonary disease (COPD), but the underlying mechanism remains unclear. Dysfunction of pulmonary surfactant proteins (SPs, including SP-A, SP-B, SP-C, and SP-D) may be included in pathophysiology of COPD. This study aimed to explore the mechanism of the integrated therapy on SPs. COPD rat models were established. The treatment groups received Bufei Yishen granules or acupoint sticking or their combination. Using aminophylline as a positive control drug. The levels of SPs in serum, BALF, and lung were measured. The results showed that the integrated therapy markedly reduced the levels of SPs in serum and increased these indicators in the lung. The integrated therapy was better than aminophylline in reducing the levels of SPs and was better than Bufei Yishen granules in reducing SP-A, SP-C, and SP-D in serum. The integrated therapy was better than aminophylline and Bufei Yishen granules in increasing SP-A, SP-B, and SP-D mRNA in the lung. SP-A and SP-D in BALF were positively correlated with PEF and EF50. The levels of SPs are associated with airway limitation. The beneficial effects of the integrated therapy may be involved in regulating pulmonary surfactant proteins. Yange Tian, Jiansheng Li, Ya Li, Yuqiong Dong, Fengjia Yao, Jing Mao, Linlin Li, Lili Wang, Shan Luo, and Minghang Wang Copyright © 2016 Yange Tian et al. All rights reserved. The Expression of NOX4 in Smooth Muscles of Small Airway Correlates with the Disease Severity of COPD Tue, 30 Aug 2016 15:34:30 +0000 Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD), and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases (NOXs) produced reactive oxygen species (ROS) play a crucial role in COPD pathogenesis. In the present study, the expression of NOX4 and its correlation with the ASM hypertrophy/hyperplasia, clinical pulmonary functions, and the expression of transforming growth factor (TGF-) in the ASM of COPD small airways were investigated by semiquantitative morphological and/or immunohistochemistry staining methods. The results showed that an elevated expression of NOX4 and TGF-, along with an increased volume of ASM mass, was found in the ASM of small airways in COPD patients. The abundance of NOX4 protein in the ASM was increased with disease severity and inversely correlated with the pulmonary functions in COPD patients. In addition, the expression of NOX4 and ASM marker α-SMA was colocalized, and the increased NOX4 expression was found to accompany an upregulated expression of TGF- in the ASM of small airways of COPD lung. These results indicate that NOX4 may be a key regulator in ASM remodeling of small airway, in part through a mechanism interacting with TGF- signaling in the pathogenesis of COPD, which warrants further investigation. Xianyan Liu, Binwei Hao, Ailing Ma, Jinxi He, Xiaoming Liu, and Juan Chen Copyright © 2016 Xianyan Liu et al. All rights reserved. Resistance to Second-Line Antituberculosis Drugs and Delay in Drug Susceptibility Testing among Multidrug-Resistant Tuberculosis Patients in Shanghai Mon, 29 Aug 2016 13:09:31 +0000 Introduction. Second-line antituberculosis drugs (SLDs) are used for treating multidrug-resistant tuberculosis (MDR-TB). Prolonged delays before confirming MDR-TB with drug susceptibility testing (DST) could result in transmission of drug-resistant strains and inappropriate use of SLDs, thereby increasing the risk of resistance to SLDs. This study investigated the diagnostic delay in DST and prevalence of baseline SLD resistance in Shanghai and described the distribution of SLD resistance with varied delays to DST. Methods. All registered patients from 2011 to 2013 in Shanghai were enrolled. Susceptibility to ofloxacin, amikacin, kanamycin, and capreomycin was tested. Total delay in DST completion was measured from the onset of symptoms to reporting DST results. Results. Resistance to SLDs was tested in 217 of the 276 MDR-TB strains, with 118 (54.4%) being resistant to at least one of the four SLDs. The median total delay in DST was 136 days. Patients with delay longer than median days were roughly twice more likely to have resistance to at least one SLD (OR 2.22, 95% CI 1.19–4.11). Conclusions. During prolonged delay in DST, primary and acquired resistance to SLDs might occur more frequently. Rapid diagnosis of MDR-TB, improved nosocomial infection controls, and regulated treatment are imperative to prevent SLD resistance. Yong Chen, Zhengan Yuan, Xin Shen, Jie Wu, Zheyuan Wu, and Biao Xu Copyright © 2016 Yong Chen et al. All rights reserved. Avian Mycobacteriosis: Still Existing Threat to Humans Sun, 31 Jul 2016 11:56:39 +0000 The nontuberculous mycobacteria are typically environmental organisms residing in soil and water. These microorganisms can cause a wide range of clinical diseases; pulmonary disease is most frequent, followed by lymphadenitis in children, skin and soft tissue disease, and rare extra pulmonary or disseminated infections. Mycobacterium avium complex is the second most common cause of pulmonary mycobacterioses after M. tuberculosis. This review covers the clinical and laboratory diagnosis of infection caused by the members of this complex and particularities for the treatment of different disease types and patient populations. Michal Slany, Vit Ulmann, and Iva Slana Copyright © 2016 Michal Slany et al. All rights reserved. N-Methyl-D-aspartate Receptor Excessive Activation Inhibited Fetal Rat Lung Development In Vivo and In Vitro Sun, 10 Jul 2016 06:51:12 +0000 Background. Intrauterine hypoxia is a common cause of fetal growth and lung development restriction. Although N-methyl-D-aspartate receptors (NMDARs) are distributed in the postnatal lung and play a role in lung injury, little is known about NMDAR’s expression and role in fetal lung development. Methods. Real-time PCR and western blotting analysis were performed to detect NMDARs between embryonic days (E) 15.5 and E21.5 in fetal rat lungs. NMDAR antagonist MK-801’s influence on intrauterine hypoxia-induced retardation of fetal lung development was tested in vivo, and NMDA’s direct effect on fetal lung development was observed using fetal lung organ culture in vitro. Results. All seven NMDARs are expressed in fetal rat lungs. Intrauterine hypoxia upregulated NMDARs expression in fetal lungs and decreased fetal body weight, lung weight, lung-weight-to-body-weight ratio, and radial alveolar count, whereas MK-801 alleviated this damage in vivo. In vitro experiments showed that NMDA decreased saccular circumference and area per unit and downregulated thyroid transcription factor-1 and surfactant protein-C mRNA expression. Conclusions. The excessive activation of NMDARs contributed to hypoxia-induced fetal lung development retardation and appropriate blockade of NMDAR might be a novel therapeutic strategy for minimizing the negative outcomes of prenatal hypoxia on lung development. Zhengchang Liao, Xiaocheng Zhou, Ziqiang Luo, Huiyi Huo, Mingjie Wang, Xiaohe Yu, Chuanding Cao, Ying Ding, Zeng Xiong, and Shaojie Yue Copyright © 2016 Zhengchang Liao et al. All rights reserved. Molecular Background of miRNA Role in Asthma and COPD: An Updated Insight Wed, 08 Jun 2016 12:22:00 +0000 Inflammatory airway diseases are a significant health problems requiring new approaches to the existing therapies and addressing fundamental issues. Difficulties in developing effective therapeutic strategies might be caused by lack of understanding of their exact molecular mechanism. MicroRNAs (miRNAs) are a class of regulators that already revolutionized the view of gene expression regulation. A cumulating number of investigations show a pivotal role of miRNAs in the pathogenesis of asthma, chronic obstructive pulmonary disease (COPD), or airway remodeling through the regulation of many pathways involved in their pathogenesis. Expression changes of several miRNAs have also been found to play a role in the development and/or improvement in asthma or COPD. Still, relatively little is known about the role of miRNAs in inflammatory disorders. The microRNA profiles may differ depending on the cell type or antigen-presenting cell. Based on the newest literature, this review discusses the current knowledge concerning miRNA contribution and influence on lung inflammation and chosen inflammatory airway diseases: asthma and COPD. Izabela Szymczak, Joanna Wieczfinska, and Rafal Pawliczak Copyright © 2016 Izabela Szymczak et al. All rights reserved. Morphologic Damage of Rat Alveolar Epithelial Type II Cells Induced by Bile Acids Could Be Ameliorated by Farnesoid X Receptor Inhibitor Z-Guggulsterone In Vitro Wed, 01 Jun 2016 13:37:24 +0000 Objective. To determine whether bile acids (BAs) affect respiratory functions through the farnesoid X receptor (FXR) expressed in the lungs and to explore the possible mechanisms of BAs-induced respiratory disorder. Methods. Primary cultured alveolar epithelial type II cells (AECIIs) of rat were treated with different concentrations of chenodeoxycholic acid (CDCA) in the presence or absence of FXR inhibitor Z-guggulsterone (GS). Then, expression of FXR in nuclei of AECIIs was assessed by immunofluorescence microscopy. And ultrastructural changes of the cells were observed under transmission electron microscope and analyzed by Image-Pro Plus software. Results. Morphologic damage of AECIIs was exhibited in high BAs group in vitro, with high-level expression of FXR, while FXR inhibitor GS could attenuate the cytotoxicity of BAs to AECIIs. Conclusions. FXR expression was related to the morphologic damage of AECIIs induced by BAs, thus influencing respiratory functions. Jieqin Wang, Yaowei Huang, Xusheng Hou, Wenyu Wu, Lei Nie, Yinghong Tian, Yanmeng Lu, and Yanru Yin Copyright © 2016 Jieqin Wang et al. All rights reserved. A Modified Carbon Monoxide Breath Test for Measuring Erythrocyte Lifespan in Small Animals Thu, 12 May 2016 12:26:36 +0000 This study was to develop a CO breath test for RBC lifespan estimation of small animals. The ribavirin induced hemolysis rabbit models were placed individually in a closed rebreath cage and air samples were collected for measurement of CO concentration. RBC lifespan was calculated from accumulated CO, blood volume, and hemoglobin concentration data. RBC lifespan was determined in the same animals with the standard biotin-labeling method. RBC lifespan data obtained by the CO breath test method for control (CON,  d) rabbits, rabbits given 10 mg/kg·d−1 of ribavirin (RIB10,  d), and rabbits given 20 mg/kg·d−1 of ribavirin (RIB20,  d) were statistically similar (all ) to and linearly correlated (, ) with the RBC lifespan data obtained for the same rabbits by the standard biotin-labeling method (CON,  d; RIB10,  d; and RIB20,  d). The CO breath test method takes less than 3 h to complete, whereas the standard method requires at least several weeks. In conclusion, the CO breath test method provides a simple and rapid means of estimating RBC lifespan and is feasible for use with small animal models. Yong-Jian Ma, Hou-De Zhang, Yong-Qiang Ji, Guo-Liang Zhu, Jia-Liang Huang, Li-Tao Du, Ping Cao, De-Yue Zang, Ji-Hui Du, Rong Li, and Lei Wang Copyright © 2016 Yong-Jian Ma et al. All rights reserved. Circulating Endocannabinoids and Insulin Resistance in Patients with Obstructive Sleep Apnea Tue, 19 Jan 2016 12:54:14 +0000 Objectives. The purpose of this study is to investigate the relationship between plasma endocannabinoids and insulin resistance (IR) in patients with obstructive sleep apnea (OSA). Methods. A population of 64 with OSA and 24 control subjects was recruited. Body mass index (BMI), waist circumference, lipids, blood glucose and insulin, homeostasis model of assessment for insulin resistance index (HOMA-IR), anandamide (AEA), 1/2-arachidonoylglycerol (1/2-AG), and apnea-hypopnea index (AHI) were analyzed. Results. Fasting blood insulin (22.9 ± 7.8 mIU/L versus 18.5 ± 7.2 mIU/L, ), HOMA-IR (2.9 ± 1.0 versus 2.4 ± 0.9, ), AEA (3.2 ± 0.7 nmol/L versus 2.5 ± 0.6 nmol/L, ), and 1/2-AG (40.8 ± 5.7 nmol/L versus 34.3 ± 7.7 nmol/L, ) were higher in OSA group than those in control group. In OSA group, AEA, 1/2-AG, and HOMA-IR increase with the OSA severity. The correlation analysis showed significant positive correlation between HOMA-IR and AHI (, ), AEA and AHI (, ), AEA and HOMA-IR (, ), and 1/2-AG and HOMA-IR (, ). Further analysis showed that only AEA was significantly correlated with AHI and HOMA-IR after adjusting for confounding factors. Conclusions. The present study indicated that plasma endocannabinoids levels, especially AEA, were associated with IR and AHI in patients with OSA. Xiaoya Wang, Qin Yu, Hongmei Yue, Jiabin Zhang, Shuang Zeng, and Fenfen Cui Copyright © 2016 Xiaoya Wang et al. All rights reserved. Hypoxia-Induced Epithelial-Mesenchymal Transition Is Involved in Bleomycin-Induced Lung Fibrosis Sun, 27 Dec 2015 12:25:59 +0000 Pulmonary fibrosis is a severe disease that contributes to the morbidity and mortality of a number of lung diseases. However, the molecular and cellular mechanisms leading to lung fibrosis are poorly understood. This study investigated the roles of epithelial-mesenchymal transition (EMT) and the associated molecular mechanisms in bleomycin-induced lung fibrosis. The bleomycin-induced fibrosis animal model was established by intratracheal injection of a single dose of bleomycin. Protein expression was measured by Western blot, immunohistochemistry, and immunofluorescence. Typical lesions of lung fibrosis were observed 1 week after bleomycin injection. A progressive increase in MMP-2, S100A4, α-SMA, HIF-1α, ZEB1, CD44, phospho-p44/42 (p-p44/42), and phospho-p38 MAPK (p-p38) protein levels as well as activation of EMT was observed in the lung tissues of bleomycin mice. Hypoxia increased HIF-1α and ZEB1 expression and activated EMT in H358 cells. Also, continuous incubation of cells under mild hypoxic conditions increased CD44, p-p44/42, and p-p38 protein levels in H358 cells, which correlated with the increase in S100A4 expression. In conclusion, bleomycin induces progressive lung fibrosis, which may be associated with activation of EMT. The fibrosis-induced hypoxia may further activate EMT in distal alveoli through a hypoxia-HIF-1α-ZEB1 pathway and promote the differentiation of lung epithelial cells into fibroblasts through phosphorylation of p38 MAPK and Erk1/2 proteins. Liang Guo, Jun-mei Xu, Lei Liu, Su-mei Liu, and Rong Zhu Copyright © 2015 Liang Guo et al. All rights reserved. Pharmacological Treatment of Idiopathic Pulmonary Fibrosis: Current Approaches, Unsolved Issues, and Future Perspectives Tue, 08 Dec 2015 11:58:59 +0000 Idiopathic pulmonary fibrosis (IPF) is a devastating condition with a 5-year survival of approximately 20%. The disease primarily occurs in elderly patients. IPF is a highly heterogeneous disorder with a clinical course that varies from prolonged periods of stability to episodes of rapid deterioration. In the last decade, improved understanding of disease mechanisms along with a more precise disease definition has allowed the design and completion of a number of high-quality clinical trials. Yet, until recently, IPF was essentially an untreatable disease. Finally, pirfenidone and nintedanib, two compounds with antifibrotic properties, have consistently proven effective in reducing functional decline and disease progression in IPF. This is a major breakthrough for patients and physicians alike, but there is still a long way to go. In fact, neither pirfenidone nor nintedanib is a cure for IPF, and most patients continue to progress despite treatment. As such, comprehensive care of patients with IPF, including management of comorbidities/complications and physical debility and timely referral for palliative care or, in a small number of highly selected patients, lung transplantation, remains essential. Several agents with high potential are currently being tested and many more are ready to be evaluated in clinical trials. Michael Kreuter, Francesco Bonella, Marlies Wijsenbeek, Toby M. Maher, and Paolo Spagnolo Copyright © 2015 Michael Kreuter et al. All rights reserved. Immunoregulation of Bone Marrow-Derived Mesenchymal Stem Cells on the Chronic Cigarette Smoking-Induced Lung Inflammation in Rats Wed, 18 Nov 2015 06:00:36 +0000 Impact of bone mesenchymal stem cell (BMSC) transfusion on chronic smoking-induced lung inflammation is poorly understood. In this study, a rat model of smoking-related lung injury was induced and the rats were treated with vehicle or BMSCs for two weeks. Different subsets of CD4+ T cells, cytokines, and anti-elastin in the lungs as well as the lung injury were characterized. Serum and lung inducible nitric oxide synthase (iNOS) and STAT5 phosphorylation in lymphocytes from lung tissue were also analyzed. Results indicated that transfusion of BMSCs significantly reduced the chronic smoking-induced lung injury, inflammation, and levels of lung anti-elastin in rats. The frequency of Th1 and Th17 cells and the levels of IL-2, IL-6, IFN-γ, TNF-α, IL-17, IP-10, and MCP-1 increased, but the frequency of Tregs and IL-10 decreased. Transfusion of BMSCs significantly modulated the imbalance of immune responses by mitigating chronic smoking-increased Th1 and Th17 responses, but enhancing Treg responses in the lungs of rats. Transfusion of BMSCs limited chronic smoking-related reduction in the levels of serum and lung iNOS and mitigated smoking-induced STAT5 phosphorylation in lymphocytes from lung tissue. BMSCs negatively regulated smoking-induced autoimmune responses in the lungs of rats and may be promising for the intervention of chronic smoking-related lung injury. Xiaoyan Li, Junyan Wang, Jing Cao, Lijuan Ma, and Jianying Xu Copyright © 2015 Xiaoyan Li et al. All rights reserved. Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases: Rationale, Aims, and Design of a Nationwide Prospective Registry—The EXCITING-ILD Registry Tue, 10 Nov 2015 06:05:54 +0000 Despite a number of prospective registries conducted in past years, the current epidemiology of interstitial lung diseases (ILD) is still not well defined, particularly regarding the prevalence and incidence, their management, healthcare utilisation needs, and healthcare-associated costs. To address these issues in Germany, a new prospective ILD registry, “Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases” (EXCITING-ILD), is being conducted by the German Centre for Lung Research in association with ambulatory, inpatient, scientific pulmonology organisations and patient support groups. This multicentre, noninterventional, prospective, and observational ILD registry aims to collect comprehensive and validated data from all healthcare institutions on the incidence, prevalence, characteristics, management, and outcomes regarding all ILD presentations in the real-world setting. Specifically, this registry will collect demographic data, disease-related data such as ILD subtype, treatments, diagnostic procedures (e.g., HRCT, surgical lung biopsy), risk factors (e.g., familial ILD), significant comorbidities, ILD managements, and disease outcomes as well as healthcare resource consumption. The EXCITING-ILD registry will include in-patient and out-patient ILD healthcare facilities in more than 100 sites. In summary, this registry will document comprehensive and current epidemiological data as well as important health economic data for ILDs in Germany. Michael Kreuter, Felix J. F. Herth, Margarethe Wacker, Reiner Leidl, Andreas Hellmann, Michael Pfeifer, Jürgen Behr, Sabine Witt, Dagmar Kauschka, Marcus Mall, Andreas Günther, and Philipp Markart Copyright © 2015 Michael Kreuter et al. All rights reserved. Understanding Idiopathic Interstitial Pneumonia: A Gene-Based Review of Stressed Lungs Sun, 11 Oct 2015 09:18:48 +0000 Pulmonary fibrosis is the main cause of severe morbidity and mortality in idiopathic interstitial pneumonias (IIP). In the past years, there has been major progress in the discovery of genetic factors that contribute to disease. Genes with highly penetrant mutations or strongly predisposing common risk alleles have been identified in familial and sporadic IIP. This review summarizes genes harbouring causative rare mutations and replicated common predisposing alleles. To date, rare mutations in nine different genes and five risk alleles fulfil this criterion. Mutated genes represent three genes involved in surfactant homeostasis and six genes involved in telomere maintenance. We summarize gene function, gene expressing cells, and pathological consequences of genetic alterations associated with disease. Consequences of the genetic alteration include dysfunctional surfactant processing, ER stress, immune dysregulation, and maintenance of telomere length. Biological evidence shows that these processes point towards a central role for alveolar epithelial type II cell dysfunction. However, tabulation also shows that function and consequence of most common risk alleles are not known. Most importantly, the predisposition of the MUC5B risk allele to disease is not understood. We propose a mechanism whereby MUC5B decreases surface tension lowering capacity of alveolar surfactant at areas with maximal mechanical stress. Coline H. M. van Moorsel, Thijs W. Hoffman, Aernoud A. van Batenburg, Dymph Klay, Joanne J. van der Vis, and Jan C. Grutters Copyright © 2015 Coline H. M. van Moorsel et al. All rights reserved. Breakdown of Epithelial Barrier Integrity and Overdrive Activation of Alveolar Epithelial Cells in the Pathogenesis of Acute Respiratory Distress Syndrome and Lung Fibrosis Wed, 07 Oct 2015 09:04:52 +0000 Individual alveolar epithelial cells (AECs) collaboratively form a tight barrier between atmosphere and fluid-filled tissue to enable normal gas exchange. The tight junctions of AECs provide intercellular sealing and are integral to the maintenance of the AEC barrier integrity. Disruption and failure of reconstitution of AEC barrier result in catastrophic consequences, leading to alveolar flooding and subsequent devastating fibrotic scarring. Recent evidences reveal that many of the fibrotic lung diseases involve AECs both as a frequent target of injury and as a driver of ongoing pathological processes. Aberrantly activated AECs express most of the growth factors and chemokines responsible for the proliferation, migration, and activation of fibroblasts. Current evidences suggest that AECs may acquire overdrive activation in the initial step of fibrosis by several mechanisms, including abnormal recapitulation of the developmental pathway, defects of the molecules essential for epithelial integrity, and acceleration of aging-related properties. Among these initial triggering events, epithelial Pten, a multiple phosphatase that negatively regulates the PI3K/Akt pathway and is crucial for lung development, is essential for the prevention of alveolar flooding and lung fibrosis through the regulation of AEC barrier integrity after injury. Reestablishment of AEC barrier integrity also involves the deployment of specialized stem/progenitor cells. Shigehisa Yanagi, Hironobu Tsubouchi, Ayako Miura, Nobuhiro Matsumoto, and Masamitsu Nakazato Copyright © 2015 Shigehisa Yanagi et al. All rights reserved. Impact of CYP1A1 Polymorphisms on Susceptibility to Chronic Obstructive Pulmonary Disease: A Meta-Analysis Thu, 03 Sep 2015 11:15:39 +0000 Objective. Several studies have evaluated the association between CYP1A1 polymorphisms and the susceptibility of chronic obstructive pulmonary disease (COPD) with inconclusive results. We performed the first comprehensive meta-analysis to summarize the association between CYP1A1 polymorphisms and COPD risk. Method. A systematic literature search was conducted (up to April 2015) in five online databases: PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), WeiPu, and WanFang databases. The strength of association was calculated by odds ratio (OR) and corresponding 95% confidence interval (CI). Results. Seven case-control studies with 1050 cases and 1202 controls were included. Our study suggested a significant association between the MspI polymorphism and COPD risk (CC versus TC + TT: OR = 1.57, CI: 1.09–2.26, ; CC versus TT: OR = 1.73, CI: 1.18–2.55, ). For the Ile/Val polymorphism, a significant association with COPD risk was observed (GG versus AG + AA: OR = 2.75, CI: 1.29–5.84, P = 0.009; GG versus AA: OR = 3.23, CI: 1.50–6.93, ; AG versus AA: OR = 1.39, CI: 1.01–1.90, ). Subgroup analysis indicated a significant association between the MspI variation and COPD risk among Asians (CC versus TC + TT: OR = 1.70, CI: 1.06–2.71, ; CC versus TT: OR = 1.84, CI: 1.11–3.06, ). Conclusion. The MspI and Ile/Val polymorphisms might alter the susceptibility of COPD, and MspI polymorphism might play a role in COPD risk among Asian population. Cheng-Di Wang, Nan Chen, Lin Huang, Jia-Rong Wang, Zhi-Yuan Chen, Ya-Mei Jiang, Ya-Zhou He, and Yu-Lin Ji Copyright © 2015 Cheng-Di Wang et al. All rights reserved. Endogenous Asymmetric Dimethylarginine Pathway in High Altitude Adapted Yaks Wed, 26 Aug 2015 09:24:05 +0000 Hypoxia-induced and high altitude pulmonary hypertension are a major problem in the mountain areas of the world. The asymmetric methylarginines (ADMA) inhibit nitric oxide (NO) synthesis by competing with L-arginine, and high levels of plasma ADMA predict adverse outcomes in pulmonary hypertension. However, little is known about the regulation of the ADMA-NO pathway in animals adapted to high altitudes. We measured the plasma ADMA concentration, endothelial NO synthase (eNOS), dimethylarginine dimethylaminohydrolases (DDAH) protein expression, and DDAH activities in the lungs from yaks. Although the yaks are hypoxemic, cardiac function and pulmonary arterial pressures are almost normal, and we found decreased DDAH expression and activity in association with reduced plasma ADMA concentrations. The eNOS expression was significantly higher in yaks. These results indicate that augmented endogenous NO activity in yaks through the ADMA-DDAH pathway and eNOS upregulation account for the low pulmonary vascular tone observed in high altitude adapted yaks. Shiro Mizuno, Takeshi Ishizaki, Hirohisa Toga, Akio Sakai, Jainagul Isakova, Elnura Taalaibekova, Zamirbek Baiserkeev, Baktybek Kojonazarov, and Almaz Aldashev Copyright © 2015 Shiro Mizuno et al. All rights reserved. Feasibility of Bioelectrical Impedance Spectroscopy Measurement before and after Thoracentesis Wed, 11 Mar 2015 08:56:43 +0000 Background. Bioelectrical impedance spectroscopy is applied to measure changes in tissue composition. The aim of this study was to evaluate its feasibility in measuring the fluid shift after thoracentesis in patients with pleural effusion. Methods. 45 participants (21 with pleural effusion and 24 healthy subjects) were included. Bioelectrical impedance was analyzed for “Transthoracic,” “Foot to Foot,” “Foot to Hand,” and “Hand to Hand” vectors in low and high frequency domain before and after thoracentesis. Healthy subjects were measured at a single time point. Results. The mean volume of removed pleural effusion was  mL. The “Foot to Foot,” “Hand to Hand,” and “Foot to Hand” vector indicated a trend for increased bioelectrical impedance after thoracentesis. Values for the low frequency domain in the “Transthoracic” vector increased significantly (). A moderate correlation was observed between the amount of removed fluid and impedance change in the low frequency domain using the “Foot to Hand” vector (). Conclusion. Bioelectrical impedance changes in correlation with the thoracic fluid level. It was feasible to monitor significant fluid shifts and loss after thoracentesis in the “Transthoracic” vector by means of bioelectrical impedance spectroscopy. The trial is registered with Registration Numbers IRB EK206/11 and NCT01778270. Matthias Daniel Zink, Sören Weyer, Karolin Pauly, Andreas Napp, Michael Dreher, Steffen Leonhardt, Nikolaus Marx, Patrick Schauerte, and Karl Mischke Copyright © 2015 Matthias Daniel Zink et al. All rights reserved. Adventitial Alterations Are the Main Features in Pulmonary Artery Remodeling due to Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats Sun, 08 Feb 2015 09:12:01 +0000 Long-term chronic intermittent exposure to altitude hypoxia is a labor phenomenon requiring further research. Using a rat model, we examined whether this type of exposure differed from chronic exposure in terms of pulmonary artery remodeling and other features. Rats were subjected to chronic hypoxia (CH, ) and long-term intermittent hypoxia (CIH2x2; 2 days of hypoxia/2 days of normoxia, ) in a chamber (428 Torr, 4,600 m of altitude) for 46 days and compared to rats under normoxia (NX, ). Body weight, hematocrit, and right ventricle ratio were measured. Pulmonary artery remodeling was assessed using confocal microscopy of tissues stained with a nuclear dye (DAPI) and CD11b antibody. Both hypoxic conditions exhibited increased hematocrit and hypertrophy of the right ventricle, tunica adventitia, and tunica media, with no changes in lumen size. The medial hypertrophy area (larger in CH) depicted a significant increase in smooth muscle cell number. Additionally, CIH2x2 increased the adventitial hypertrophy area, with an increased cellularity and a larger prevalence of clustered inflammatory cells. In conclusion, CIH2x2 elicits milder effects on pulmonary artery medial layer muscularization and subsequent right ventricular hypertrophy than CH. However, CIH2x2 induces greater and characteristic alterations of the adventitial layer. Julio Brito, Patricia Siques, Silvia M. Arribas, Angel L. López de Pablo, M. Carmen González, Nelson Naveas, Karem Arriaza, Karen Flores, Fabiola León-Velarde, Ruth Pulido, Stefany Ordenes, and M. Rosario López Copyright © 2015 Julio Brito et al. All rights reserved. Flail Chest in Polytraumatized Patients: Surgical Fixation Using Stracos Reduces Ventilator Time and Hospital Stay Sun, 01 Feb 2015 09:59:00 +0000 Objectives. Conservative management of patients with flail chest is the treatment of choice. Rib fracture repair is technically challenging; however, with the advent of specially designed molding titanium clips, surgical management has been simplified. Surgical stabilization has been used with good outcomes. We are reporting on our institutional matched-case-control study. Methods. Between April 2010 and April 2011, ten polytraumatized patients undergoing rib stabilization for flail chest were matched 1 : 1 to 10 control patients by age 10 years, sex, neurological or vertebral trauma, abdominal injury, and arm and leg fractures. Surgery was realized in the first 48 hours. Results. There were no significant differences between groups for matched data and prognostic scores: injury severity score, revised trauma score, and trauma injury severity score. Ventilator time (142  224 versus 74  125 hours, ) and overall hospital stay (142  224 versus 74  125 hours, ) were significantly lower for the surgical group after adjustment on prognostic scores. There was a trend towards shorter ICU stay for operative patients (12.3  8.5 versus 9.0  4.3 days, ). Conclusions. Rib fixation with Stracos is feasible and decreases the length of ventilation and hospital stay. A multicenter randomized study is warranted so as to confirm these results and to evaluate impact on pulmonary function status, pain, and quality of life. Christophe P. M. Jayle, Géraldine Allain, Pierre Ingrand, Leila Laksiri, Emilie Bonnin, Jamil Hajj-Chahine, Olivier Mimoz, and Pierre Corbi Copyright © 2015 Christophe P. M. Jayle et al. All rights reserved. A New Mechanism of Vitamin C Effects on A/FM/1/47(H1N1) Virus-Induced Pneumonia in Restraint-Stressed Mice Sun, 01 Feb 2015 09:21:51 +0000 It is well known that vitamin C could protect against influenza infection, but little is known about the mechanisms. This study aimed to investigate the influence and possible mechanisms of vitamin C on pneumonia induced by influenza virus in stressed mice. Results showed that restraint stress significantly increased the mortality and the severity of pneumonia in mice caused by A/FM/1/47(H1N1) virus infection, which was attenuated by oral administration of vitamin C (125 and 250 mg/kg). Moreover, vitamin C administration significantly decreased expression of susceptibility genes, including mitochondrial antiviral signaling (MAVS) and interferon regulatory factor 3 (IRF3), and increased expression of NF-κB. These work in conjunction to induce type I interferons (IFNs) and elicit innate antiviral response as key factors in RIG-I-mediated signal transduction pathway. The above effects of vitamin C were further found to relate with inhibition of excess CORT synthesis by regulating steroid hydroxylating enzymes in adrenal gland. In conclusion, the protective effects of vitamin C on influenza virus-caused pneumonia might be related to its inhibition of CORT synthesis, which reduces the susceptibility to influenza viral infection in restraint-stressed mice. These findings provide a new mechanism for the effects of vitamin C on influenza virus-induced pneumonia in restraint-stressed mice. Ying Cai, Yi-Fang Li, Lu-Ping Tang, Bun Tsoi, Min Chen, Huan Chen, Xiao-Mei Chen, Rui-Rong Tan, Hiroshi Kurihara, and Rong-Rong He Copyright © 2015 Ying Cai et al. All rights reserved. Activity of α1-Antitrypsin and Some Lysosomal Enzymes in the Blood Serum of Patients with Chronic Obstructive Pulmonary Disease after Smoking Cessation Sat, 31 Jan 2015 12:49:21 +0000 The activity of α1-antitrypsin (AAT) and the lysosomal enzymes, cathepsin D (CTS D), arylsulfatase (ASA), and acid phosphatase, (AcP) was determined in patients with COPD (GOLD category A). Moreover, the diagnostic usefulness of these parameters in blood serum was assessed along with establishing whether smoking cessation affects these parameters. The study included 70 patients with COPD who ceased smoking (study group) and two control groups of 33 subjects each: nonsmokers without COPD (control I) and patients with COPD who continued smoking (control II). In control I, blood was taken once and in control II, at the start of the experiment and after the 1st, 2nd, and 3rd months. AAT in the patients exhibited higher activity than in the healthy subjects at all time points. AAT activity in the patients before the start of the experiment was 80% higher () than in control I. No statistically significant differences in CTS D, ASA, and AcP activity were found. COPD involves increased AAT activity and unchanged activities of the assessed lysosomal enzymes. Three-month tobacco abstinence does not affect these parameters in peripheral blood. Determining the AAT levels in blood serum can be used in the diagnostics of COPD. Bartosz Woźniak, Alina Woźniak, Jacek Konca, Dariusz Górecki, Celestyna Mila-Kierzenkowska, Michał Szpinda, Paweł Sutkowy, and Roland Wesołowski Copyright © 2015 Bartosz Woźniak et al. All rights reserved. Potential Therapeutic Benefit of Combining Gefitinib and Tamoxifen for Treating Advanced Lung Adenocarcinoma Mon, 26 Jan 2015 06:50:28 +0000 Introduction. Epidermal growth factor receptor (EGFR) mutations are known as oncogene driver mutations and with EGFR mutations exhibit good response to the EGFR tyrosine kinase inhibitor Gefitinib. Some studies have shown that activation of estrogen and estrogen receptor α or β (ERα/β) promote adenocarcinoma. We evaluated the relationship between the two receptors and the potential therapeutic benefit with Gefitinib and Tamoxifen. Methods. We assessed the association between EGFR mutations as well as ERα/β expression/location and overall survival in a cohort of 55 patients with LAC from a single hospital. PC9 (EGFR exon 19 deletion mutant; Gefitinib-vulnerable cells) and A549 (EGFR wild type; Gefitinib-resistant cells) cancer cells were used to evaluate the in vitro therapeutic benefits of combining Gefitinib and Tamoxifen. Results. We found that the cytosolic but not the nuclear expression of ERβ was associated with better OS in LAC tumors but not associated with EGFR mutation. The in vitro study showed that combined Gefitinib and Tamoxifen resulted in increased apoptosis and cytosolic expression of ERβ. In addition, combining both medications resulted in reduced cell growth and increased the cytotoxic effect of Gefitinib. Conclusion. Tamoxifen enhanced advanced LAC cytotoxic effect induced by Gefitinib by arresting ERβ in cytosol. Chien-Ming Liu, Kuo-Liang Chiu, Tzu-Sheng Chen, Shang-Miao Chang, Shu-Yun Yang, Li-Hsiou Chen, Yung-Lun Ni, Yuh-Pyng Sher, Sung-Liang Yu, and Wen-Lung Ma Copyright © 2015 Chien-Ming Liu et al. All rights reserved. Utility of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Diagnosis of Intrathoracic Lymphadenopathy in Patients with Human Immunodeficiency Virus Infection Wed, 14 Jan 2015 14:30:25 +0000 Objective. Intrathoracic lymphadenopathy (LAD) in patients with Human Immunodeficiency Virus (HIV) infection is common, with wide-ranging diagnoses, from benign to malignant causes. Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) is a relatively new technology with established applications in lung cancer, sarcoidosis, and tuberculosis. We sought to find out whether the addition of EBUS-TBNA to the diagnostic algorithm for LAD in HIV patients will reduce the need for mediastinoscopy. Methods. Retrospective chart review of all EBUS-TBNA procedures performed in our centre from August 2008 to December 2012. Results. 513 patients had EBUS-TBNA performed during this period. We identified nine HIV-infected patients who had LAD of unknown cause and underwent EBUS-TBNA. The procedure reduced the need for mediastinoscopy in eight patients (89%). Conclusions. Potential mediastinoscopies can be avoided by utilising EBUS-TBNA in HIV patients with LAD. Audrey Yan Yi Han, Aik Hau Tan, and Mariko Siyue Koh Copyright © 2015 Audrey Yan Yi Han et al. All rights reserved. Blunted Activation of Rho-Kinase in Yak Pulmonary Circulation Wed, 14 Jan 2015 14:16:14 +0000 Yaks have adapted to high altitude and they do not develop hypoxic pulmonary hypertension. Although we previously identified the important role of augmented nitric oxide synthase activity in the yak pulmonary circulatory system, evidence of the direct involvement of Rho-kinase as a basal vascular tone regulator is lacking. Four domesticated male pure-bred yaks and four bulls that were born and raised at an altitude of 3000 m in the Tien-Shan mountains were studied at an altitude of 3,100 m. Mean pulmonary artery pressure (mPAP) was measured before and after fasudil (60 mg in 20 mL of saline) was intravenously administered using a Swan-Ganz catheter at a rate of 3.3 mL/min for 30 min. Fasudil decreased mPAP in bulls from to  mmHg () after 15 min and the level was maintained for 30 min, but it merely blunted mPAP in yaks from to and  mmHg after 5 and 30 min, respectively. These findings comprise the first evidence of a modest role of Rho-kinase in the maintenance of pulmonary artery pressure in the yak. Takeshi Ishizaki, Shiro Mizuno, Akio Sakai, Shigeru Matsukawa, Baktybek Kojonazarov, Baiserkeev Zamirbek, Yukihiro Umeda, Miwa Morikawa, Masaki Anzai, Tamotsu Ishizuka, and Almaz Aldashev Copyright © 2015 Takeshi Ishizaki et al. All rights reserved. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure Wed, 14 Jan 2015 14:01:57 +0000 Objective. The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF. Wiebke Janssen, Yves Schymura, Tatyana Novoyatleva, Baktybek Kojonazarov, Mario Boehm, Astrid Wietelmann, Himal Luitel, Kirsten Murmann, Damian Richard Krompiec, Aleksandra Tretyn, Soni Savai Pullamsetti, Norbert Weissmann, Werner Seeger, Hossein Ardeschir Ghofrani, and Ralph Theo Schermuly Copyright © 2015 Wiebke Janssen et al. All rights reserved. A Single Imaging Modality in the Diagnosis, Severity, and Prognosis of Pulmonary Embolism Sun, 14 Dec 2014 12:19:42 +0000 Introduction. This study aimed to investigate the currency of computerized tomography pulmonary angiography-based parameters as pulmonary artery obstruction index (PAOI), as well as right ventricular diameters for pulmonary embolism (PE) risk evaluation and prediction of mortality and intensive care unit (ICU) requirement. Materials and Methods. The study retrospectively enrolled 203 patients hospitalized with acute PE. PAOI was calculated according to Qanadli score. Results. Forty-three patients (23.9%) were hospitalized in the ICU. Nineteen patients (10.6%) died during the 30-day follow-up period. The optimal cutoff value of PAOI for PE 30th day mortality and ICU requirement were found as 36.5% in ROC curve analysis. The pulmonary artery systolic pressure had a significant positive correlation with right/left ventricular diameter ratio (, ), PAOI (, ), and pulmonary artery diameter (, ). The patients with PAOI values higher than 36.5% have a 5.7-times increased risk of death. Conclusion. PAOI is a fast and promising parameter for risk assessment in patients with acute PE. With greater education of clinicians in this radiological scoring, a rapid assessment for diagnosis, clinical risk evaluation, and prognosis may be possible in emergency services without the need for echocardiography. Hadice Selimoglu Sen, Özlem Abakay, Mehmet Güli Cetincakmak, Cengizhan Sezgi, Süreyya Yilmaz, Melike Demir, Mahsuk Taylan, and Hatice Gümüs Copyright © 2014 Hadice Selimoglu Sen et al. All rights reserved. Prognostic Implication of Predominant Histologic Subtypes of Lymph Node Metastases in Surgically Resected Lung Adenocarcinoma Sun, 12 Oct 2014 08:06:24 +0000 The International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) proposed a new classification for lung adenocarcinoma (AD) based on predominant histologic subtypes, such as lepidic, papillary, acinar, solid, and micropapillary; this system reportedly reflects well outcomes of patients with surgically resected lung AD. However, the prognostic implication of predominant histologic subtypes in lymph nodes metastases is unclear so far. In this study, we compared predominant subtypes between primary lung tumors and lymph node metastatic lesions in 24 patients with surgically treated lung adenocarcinoma with lymph node metastases. Additionally, we analyzed prognostic implications of these predominant histologic subtypes. We observed several discordance patterns between predominant subtypes in primary lung tumors and lymph node metastases. Concordance rates were 22%, 64%, and 100%, respectively, in papillary-, acinar-, and solid-predominant primary lung tumors. We observed that the predominant subtype in the primary lung tumor (HR 12.7, ), but not that in lymph node metastases (HR 0.18, ), determines outcomes in patients with surgically resected lung AD with lymph node metastases. Kenichi Suda, Katsuaki Sato, Shigeki Shimizu, Kenji Tomizawa, Toshiki Takemoto, Takuya Iwasaki, Masahiro Sakaguchi, and Tetsuya Mitsudomi Copyright © 2014 Kenichi Suda et al. All rights reserved. Carbon Ion Therapy for Early-Stage Non-Small-Cell Lung Cancer Thu, 11 Sep 2014 00:00:00 +0000 Carbon ion therapy is a type of radiotherapies that can deliver high-dose radiation to a tumor while minimizing the dose delivered to the organs at risk; this profile differs from that of photon radiotherapy. Moreover, carbon ions are classified as high-linear energy transfer radiation and are expected to be effective for even photon-resistant tumors. Recently, high-precision radiotherapy modalities such as stereotactic body radiotherapy (SBRT), proton therapy, and carbon ion therapy have been used for patients with early-stage non-small-cell lung cancer, and the results are promising, as, for carbon ion therapy, local control and overall survival rates at 5 years are 80–90% and 40–50%, respectively. Carbon ion therapy may be theoretically superior to SBRT and proton therapy, but the literature that is currently available does not show a statistically significant difference among these treatments. Carbon ion therapy demonstrates a better dose distribution than both SBRT and proton therapy in most cases of early-stage lung cancer. Therefore, carbon ion therapy may be safer for treating patients with adverse conditions such as large tumors, central tumors, and poor pulmonary function. Furthermore, carbon ion therapy may also be suitable for dose escalation and hypofractionation. Yusuke Demizu, Osamu Fujii, Hiromitsu Iwata, and Nobukazu Fuwa Copyright © 2014 Yusuke Demizu et al. All rights reserved. Pulmonary Hypertension and Right Heart Dysfunction in Chronic Lung Disease Thu, 24 Jul 2014 08:58:17 +0000 Group 3 pulmonary hypertension (PH) is a common complication of chronic lung disease (CLD), including chronic obstructive pulmonary disease (COPD), interstitial lung disease, and sleep-disordered breathing. Development of PH is associated with poor prognosis and may progress to right heart failure, however, in the majority of the patients with CLD, PH is mild to moderate and only a small number of patients develop severe PH. The pathophysiology of PH in CLD is multifactorial and includes hypoxic pulmonary vasoconstriction, pulmonary vascular remodeling, small vessel destruction, and fibrosis. The effects of PH on the right ventricle (RV) range between early RV remodeling, hypertrophy, dilatation, and eventual failure with associated increased mortality. The golden standard for diagnosis of PH is right heart catheterization, however, evidence of PH can be appreciated on clinical examination, serology, radiological imaging, and Doppler echocardiography. Treatment of PH in CLD focuses on management of the underlying lung disorder and hypoxia. There is, however, limited evidence to suggest that PH-specific vasodilators such as phosphodiesterase-type 5 inhibitors, endothelin receptor antagonists, and prostanoids may have a role in the treatment of patients with CLD and moderate-to-severe PH. Amirmasoud Zangiabadi, Carmine G. De Pasquale, and Dimitar Sajkov Copyright © 2014 Amirmasoud Zangiabadi et al. All rights reserved. Effects of a Pragmatic Lifestyle Intervention for Reducing Body Mass in Obese Adults with Obstructive Sleep Apnoea: A Randomised Controlled Trial Mon, 21 Jul 2014 00:00:00 +0000 This study investigated the effects of a pragmatic lifestyle intervention in obese adults with continuous positive airway pressure-treated obstructive sleep apnoea hypopnoea syndrome (OSAHS). Sixty patients were randomised 1 : 1 to either a 12-week lifestyle intervention or an advice-only control group. The intervention involved supervised exercise sessions, dietary advice, and the promotion of lifestyle behaviour change using cognitive-behavioural techniques. Outcomes were assessed at baseline (week 0), intervention end-point (week 13), and follow-up (week 26). The primary outcome was 13-week change in body mass. Secondary outcomes included anthropometry, blood-borne biomarkers, exercise capacity, and health-related quality of life. At end-point, the intervention group exhibited small reductions in body mass (−1.8 [−3.0, −0.5] kg; ) and body fat percentage (−1 [−2, 0]%; ) and moderate improvements in C-reactive protein (−1.3 [−2.4, −0.2] mg·L−1; ) and exercise capacity (95 [50, 139] m; ). At follow-up, changes in body mass (−2.0 [−3.5, −0.5] kg; ), body fat percentage (−1 [−2, 0]%; ), and C-reactive protein (−1.3 [−2.5, −0.1] mg·L−1; ) were maintained and exercise capacity was further improved (132 [90, 175] m; ). This trial is registered with NCT01546792. James Moss, Garry Alan Tew, Robert James Copeland, Martin Stout, Catherine Grant Billings, John Michael Saxton, Edward Mitchell Winter, and Stephen Mark Bianchi Copyright © 2014 James Moss et al. All rights reserved. Proton-Based Stereotactic Ablative Radiotherapy in Early-Stage Non-Small-Cell Lung Cancer Thu, 17 Jul 2014 12:13:31 +0000 Stereotactic ablative radiotherapy (SABR), a recent implementation in the practice of radiation oncology, has been shown to confer high rates of local control in the treatment of early stage non-small-cell lung cancer (NSCLC). This technique, which involves limited invasive procedures and reduced treatment intervals, offers definitive treatment for patients unable or unwilling to undergo an operation. The use of protons in SABR delivery confers the added physical advantage of normal tissue sparing due to the absence of collateral radiation dose delivered to regions distal to the target. This may translate into clinical benefit and a decreased risk of clinical toxicity in patients with nearby critical structures or limited pulmonary reserve. In this review, we present the rationale for proton-based SABR, principles relating to the delivery and planning of this modality, and a summary of published clinical studies. Jonathan D. Grant and Joe Y. Chang Copyright © 2014 Jonathan D. Grant and Joe Y. Chang. All rights reserved. Stereotactic Body Radiotherapy for Small Lung Tumors in the University of Tokyo Hospital Mon, 07 Jul 2014 11:10:14 +0000 Our work on stereotactic body radiation therapy (SBRT) for primary and metastatic lung tumors will be described. The eligibility criteria for SBRT, our previous SBRT method, the definition of target volume, heterogeneity correction, the position adjustment using four-dimensional cone-beam computed tomography (4D CBCT) immediately before SBRT, volumetric modulated arc therapy (VMAT) method for SBRT, verifying of tumor position within internal target volume (ITV) using in-treatment 4D-CBCT during VMAT-SBRT, shortening of treatment time using flattening-filter-free (FFF) techniques, delivery of 4D dose calculation for lung-VMAT patients using in-treatment CBCT and LINAC log data with agility multileaf collimator, and SBRT method for centrally located lung tumors in our institution will be shown. In our institution, these efforts have been made with the goal of raising the local control rate and decreasing adverse effects after SBRT. Hideomi Yamashita, Wataru Takahashi, Akihiro Haga, Satoshi Kida, Naoya Saotome, and Keiichi Nakagawa Copyright © 2014 Hideomi Yamashita et al. All rights reserved. Circulating Endothelial-Derived Activated Microparticle: A Useful Biomarker for Predicting One-Year Mortality in Patients with Advanced Non-Small Cell Lung Cancer Sun, 29 Jun 2014 07:56:30 +0000 Background. This study tested the hypothesis that circulating microparticles (MPs) are useful biomarkers for predicting one-year mortality in patients with end-stage non-small cell lung cancer (ES-NSCLC). Methods and Results. One hundred seven patients were prospectively enrolled into the study between April 2011 and February 2012, and each patient received regular follow-up after enrollment. Levels of four MPs in circulation, (1) platelet-derived activated MPs (PDAc-MPs), (2) platelet-derived apoptotic MPs (PDAp-MPs), (3) endothelial-derived activated MPs (EDAc-MPs), and (4) endothelial-derived apoptotic MPs (EDAp-MPs), were measured just after the patient was enrolled into the study using flow cytometry. Patients who survived for more than one year were categorized into group 1 (one-year survivors) and patients who survived less than one year were categorized into group 2 (one-year nonsurvivors). Male gender, incidence of liver metastasis, progression of disease after first-line treatment, poor performance status, and the Charlson comorbidity index were significantly higher in group 2 than in group 1 (all ). Additionally, as measured by flow cytometry, only the circulating level of EDAc-MPs was found to be significantly higher in group 2 than in group 1 . Multivariate analysis demonstrated that circulating level of EDAc-MPs along with brain metastasis and male gender significantly and independently predictive of one-year mortality (all ). Conclusion. Circulating EDAc-MPs may be a useful biomarker predictive of one-year morality in ES-NSCLC patients. Chin-Chou Wang, Chia-Cheng Tseng, Chang-Chun Hsiao, Huang-Chih Chang, Li-Teh Chang, Wen-Feng Fang, Steve Leu, Yi-Hsi Wang, Tzu-Hsien Tsai, Cheng-Ta Yang, Chih-Hung Chen, Hon-Kan Yip, Chi-Kung Ho, and Meng-Chih Lin Copyright © 2014 Chin-Chou Wang et al. All rights reserved. Humidification during Mechanical Ventilation in the Adult Patient Wed, 25 Jun 2014 10:48:21 +0000 Humidification of inhaled gases has been standard of care in mechanical ventilation for a long period of time. More than a century ago, a variety of reports described important airway damage by applying dry gases during artificial ventilation. Consequently, respiratory care providers have been utilizing external humidifiers to compensate for the lack of natural humidification mechanisms when the upper airway is bypassed. Particularly, active and passive humidification devices have rapidly evolved. Sophisticated systems composed of reservoirs, wires, heating devices, and other elements have become part of our usual armamentarium in the intensive care unit. Therefore, basic knowledge of the mechanisms of action of each of these devices, as well as their advantages and disadvantages, becomes a necessity for the respiratory care and intensive care practitioner. In this paper, we review current methods of airway humidification during invasive mechanical ventilation of adult patients. We describe a variety of devices and describe the eventual applications according to specific clinical conditions. Haitham S. Al Ashry and Ariel M. Modrykamien Copyright © 2014 Haitham S. Al Ashry and Ariel M. Modrykamien. All rights reserved. Right Heart Functional Changes in the Acute, Hypercapnic Exacerbations of COPD Mon, 23 Jun 2014 05:42:37 +0000 Objective. To investigate the correlation between respiratory failure and the pulmonary circulation. We focused on anatomical and functional changes of the right heart. Design. Clinical investigation. Methods. We evaluated 75 patients hospitalized in our respiratory ward for COPD exacerbation. All patients underwent transthoracic echocardiography and measurements of right heart chambers. Moreover all patients underwent blood tests, measurement of blood pressure, evaluation of body mass index (BMI), ECGs, pulmonary function tests, and the Saint George’s Respiratory Questionnaire (SGRQ). Results. Among 75 patients consecutively hospitalized, 56 patients with a COPD exacerbation were included in our study. We have emphasized the higher value of PAPs and the increased size of right atrial area in severe COPD patients. Significant correlation was observed between low values of PaO2 and larger area of the right atrium. The measurement of TAPSE showed a right ventricular dysfunction in all patients but especially in severe COPD patients. We have obtained a significant correlation between TAPSE and arterial blood gas. Conclusions. In patients with chronic respiratory failure, blood gas parameters should be considered as negative prognostic factors of right heart failure. Respiratory failure shows a relationship with pulmonary hypertension and with the anatomy and function of the right heart sections. Claudio Terzano, Sofia Romani, Carlo Gaudio, Francesco Pelliccia, Mattia Serao, and Antonio Vitarelli Copyright © 2014 Claudio Terzano et al. All rights reserved. Second- and Further-Line Therapy with Erlotinib in Patients with Advanced Non-Small-Cell Lung Cancer in Daily Clinical Practice Tue, 17 Jun 2014 00:00:00 +0000 Introduction. The aim of this retrospective study was to examine effect of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) in second-line and further therapy in daily clinical practice. Methods. Patients with histologically or cytologically proven NSCLC () treated with erlotinib in second-line (), third-line (), and more-line therapy () were examined for progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of therapy, and adverse effects. Results. Median PFS of all lines was 83 days (CI 70.0–96.0), OS was 7 months (CI 4.7–9.3), DCR was 66.2% (CI 55–77%), and 1-year survival rate was 33% (CI 22–43%), with no significant difference between therapy lines. Median duration of treatment was 76 days (IQR 39–139.5). Patients with epidermal growth factor receptor mutation (EGFR-M) reached the highest PFS (204 days), as did patients with good performance status (ECOG 0-1: 94 versus ECOG 2-3: 65 days, ). Patients with EGFR-M also revealed a DCR of 100%. The most frequent side effects were rash (69%) and diarrhoea (41%), without any significant difference between therapy lines. In 24 patients, the treatment dose was reduced and in 18, the therapy was paused. Conclusion. Erlotinib works in all therapy lines without any significant differences in efficacy and side effects. Josephine Krainhöfer, Mario Walther, Matthias Steinert, and Angelika Reissig Copyright © 2014 Josephine Krainhöfer et al. All rights reserved. Treatment of Acute Pulmonary Embolism: Update on Newer Pharmacologic and Interventional Strategies Sun, 15 Jun 2014 11:38:23 +0000 Acute pulmonary embolism (PE) is a common complication in hospitalized patients, spanning multiple patient populations and crossing various therapeutic disciplines. Current treatment paradigm in patients with massive PE mandates prompt risk stratification with aggressive therapeutic strategies. With the advent of endovascular technologies, various catheter-based thrombectomy and thrombolytic devices are available to treat patients with massive or submassive PE. In this paper, a variety of newer treatment strategies for PE are analyzed, with special emphasis on various interventional treatment strategies. Clinical evidence for utilizing endovascular treatment modalities, based on our institutional experience as well as a literature review, is provided. Francesco Pelliccia, Michele Schiariti, Claudio Terzano, Abdul M. Keylani, Darrin C. D'Agostino, Giuseppe Speziale, Cesare Greco, and Carlo Gaudio Copyright © 2014 Francesco Pelliccia et al. All rights reserved. Ibuprofen Protects Ventilator-Induced Lung Injury by Downregulating Rho-Kinase Activity in Rats Thu, 12 Jun 2014 09:07:31 +0000 Background. Ventilator-induced lung injury-(VILI-) induced endothelial permeability is regulated through the Rho-dependent signaling pathway. Ibuprofen inhibits Rho activation in animal models of spinal-cord injury and Alzheimer’s disease. The study aims to investigate ibuprofen effects on high tidal volume associated VILI. Methods. Twenty-eight adult male Sprague-Dawley rats were randomized to receive a ventilation strategy with three different interventions for 2 h: (1) a high-volume zero-positive end-expiratory pressure (PEEP) (HVZP) group; (2) an HVZP + ibuprofen 15 mg/kg group; and (3) an HVZP + ibuprofen 30 mg/kg group. A fourth group without ventilation served as the control group. Rho-kinase activity was determined by ratio of phosphorylated ezrin, radixin, and moesin (p-ERM), substrates of Rho-kinase, to total ERM. VILI was characterized by increased pulmonary protein leak, wet-to-dry weight ratio, cytokines level, and Rho guanine nucleotide exchange factor (GEF-H1), RhoA activity, p-ERM/total ERM, and p-myosin light chain (MLC) protein expression. Results. Ibuprofen pretreatment significantly reduced the HVZP ventilation-induced increase in pulmonary protein leak, wet-to-dry weight ratio, bronchoalveolar lavage fluid interleukin-6 and RANTES levels, and lung GEF-H1, RhoA activity, p-ERM/total ERM, and p-MLC protein expression. Conclusion. Ibuprofen attenuated high tidal volume induced pulmonary endothelial hyperpermeability. This protective effect was associated with a reduced Rho-kinase activity. Liang-Ti Huang, Chien-Huang Lin, Hsiu-Chu Chou, and Chung-Ming Chen Copyright © 2014 Liang-Ti Huang et al. All rights reserved. Pulmonary Arterial Hypertension in Adults: Novel Drugs and Catheter Ablation Techniques Show Promise? Systematic Review on Pharmacotherapy and Interventional Strategies Thu, 12 Jun 2014 00:00:00 +0000 This systematic review aims to provide an update on pharmacological and interventional strategies for the treatment of pulmonary arterial hypertension in adults. Currently US Food and Drug Administration approved drugs including prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and soluble guanylate-cyclase stimulators. These agents have transformed the prognosis for pulmonary arterial hypertension patients from symptomatic improvements in exercise tolerance ten years ago to delayed disease progression today. On the other hand, percutaneous balloon atrioseptostomy by using radiofrequency perforation, cutting balloon dilatation, or insertion of butterfly stents and pulmonary artery catheter-based denervation, both associated with very low rate of major complications and death, should be considered in combination with specific drugs at an earlier stage rather than late in the progression of pulmonary arterial hypertension and before the occurrence of overt right-sided heart failure. Salvatore Rosanio, Francesco Pelliccia, Carlo Gaudio, Cesare Greco, Abdul M. Keylani, and Darrin C. D’Agostino Copyright © 2014 Salvatore Rosanio et al. All rights reserved. The Increased Type-1 and Type-2 Chemokine Levels in Children with Acute RSV Infection Alter the Development of Adaptive Immune Responses Wed, 11 Jun 2014 09:37:34 +0000 Severe RSV infections and frequent recurrence could be related to the altered polarization of type-2/type-1 T cells. This increases the importance of determining distinctive chemokines and chemokine receptor profiles on memory T cells. We analyzed systemic adaptive T cell response in the acute () and convalescent phase () of RSV-infected children, in the acute () and convalescent phase () of children with other viral respiratory infections (adenovirus and influenza virus), and in healthy children (). Expression of CCR4 and CXCR3 on effector-memory (TEM) and central-memory (TCM) T cells was compared between tested groups. Serum concentrations of specific chemokines were determined. High CXCL10 levels were detected in acutely infected children regardless of virus pathogen, whereas increased CCL17 production was RSV-specific. Higher percentages of CCR4+ CD4 TEM cells in acute RSV infection were accompanied with higher percentages of CXCR3+ CD8 TEM cells, whereas the development of long-lived memory CXCR3+ CD4 and CD8 TCM cells seems to be compromised, as only children with other viral infections had higher percentages in the convalescent phase. Presence of type-2 and type-1 adaptive antiviral immune response, together with insufficient development of long-lived type-1 T cell memory, could play an important role in RSV pathogenesis and reinfection. Valerija Vojvoda, Ana Savić Mlakar, Mladen Jergović, Mirela Kukuruzović, Leo Markovinović, Neda Aberle, Sabina Rabatić, and Krešo Bendelja Copyright © 2014 Valerija Vojvoda et al. All rights reserved. Parasitic Pneumonia and Lung Involvement Mon, 09 Jun 2014 00:00:00 +0000 Parasitic infestations demonstrated a decline in the past decade as a result of better hygiene practices and improved socioeconomic conditions. Nevertheless, global immigration, increased numbers of the immunocompromised people, international traveling, global warming, and rapid urbanization of the cities have increased the susceptibility of the world population to parasitic diseases. A number of new human parasites, such as Plasmodium knowlesi, in addition to many potential parasites, have urged the interest of scientific community. A broad spectrum of protozoal parasites frequently affects the respiratory system, particularly the lungs. The diagnosis of parasitic diseases of airway is challenging due to their wide varieties of clinical and roentgenographic presentations. So detailed interrogations of travel history to endemic areas are critical for clinicians or pulmonologists to manage this entity. The migrating adult worms can cause mechanical airway obstruction, while the larvae can cause airway inflammation. This paper provides a comprehensive review of both protozoal and helminthic infestations that affect the airway system, particularly the lungs, including clinical and roentgenographic presentations, diagnostic tests, and therapeutic approaches. Attapon Cheepsattayakorn and Ruangrong Cheepsattayakorn Copyright © 2014 Attapon Cheepsattayakorn and Ruangrong Cheepsattayakorn. All rights reserved. Safety and Efficacy of Intensity-Modulated Stereotactic Body Radiotherapy Using Helical Tomotherapy for Lung Cancer and Lung Metastasis Wed, 04 Jun 2014 12:27:43 +0000 Stereotactic body radiotherapy (SBRT) proved to be an effective treatment with acceptable toxicity for lung tumors. However, the use of helical intensity-modulated (IM) SBRT is controversial. We investigated the outcome of lung tumor patients treated by IMSBRT using helical tomotherapy with a Japanese standard fractionation schedule of 48 Gy in 4 fractions () or modified protocols of 50–60 Gy in 5–8 fractions (). Median patient’s age was 76 years and median follow-up period for living patients was 20 months (range, 6–46). The median PTV was 6.9 cc in the 4-fraction group and 14 cc in the 5- to 8-fraction group (). Grade 2 radiation pneumonitis was seen in 2 of 37 patients in the 4-fraction group and in 2 of 35 patients in the 5- to 8-fraction group (log-rank ). Other major complications were not observed. The LC rates at 2 years were 87% in the 4-fraction group and 83% in the 5- to 8-fraction group. Helical IMSBRT for lung tumors is safe and effective. Patients with a high risk of developing severe complications may also be safely treated using 5–8 fractions. The results of the current study warrant further studies of helical IMSBRT. Aiko Nagai, Yuta Shibamoto, Masanori Yoshida, Koji Inoda, and Yuzo Kikuchi Copyright © 2014 Aiko Nagai et al. All rights reserved. Cryoablation of Early-Stage Primary Lung Cancer Wed, 04 Jun 2014 07:29:24 +0000 Worldwide, lung cancer is the most commonly diagnosed cancer, and lobectomy is the gold-standard treatment for early-stage non-small cell lung cancer (NSCLC). However, many patients are poor surgical candidates for various reasons. Recently, image-guided ablation is being used for lung tumors. Cryoablation has been applied for the treatment of cancer in various nonaerated organs; recently it has been adapted to the treatment of lung tumors. Since an ice ball can be detected by computed tomography (CT), cryoablation of lung tumors is performed under CT guidance. Its first clinical application was reported in 2005, and it has been reported to be feasible in a few studies. Minor complications occurred at a high frequency (up to 70.5%), but major complications were rare (up to 1%). The most common complication is pneumothorax, and most cases need no further intervention. Local efficacy depends on tumor size and presence of a thick vessel close to the tumor. Midterm survival after cryoablation is 77%–88% at 3 years in patients with early-stage NSCLC. Although surgery is the gold-standard treatment for such patients, the initial results of cryoablation are promising. In this paper, the current status of cryoablation for primary lung tumors is reviewed. Masanori Inoue, Seishi Nakatsuka, and Masahiro Jinzaki Copyright © 2014 Masanori Inoue et al. All rights reserved. Radiofrequency Ablation for Early-Stage Nonsmall Cell Lung Cancer Tue, 03 Jun 2014 11:13:27 +0000 This review examines studies of radiofrequency ablation (RFA) of nonsmall cell lung cancer (NSCLC) and discusses the role of RFA in treatment of early-stage NSCLC. RFA is usually performed under local anesthesia with computed tomography guidance. RFA-associated mortality, while being rare, can result from pulmonary events. RFA causes pneumothorax in up to 63% of cases, although pneumothorax requiring chest drainage occurs in less than 15% of procedures. Other severe complications are rare. After RFA of stage I NSCLC, 31–42% of patients show local progression. The 1-, 2-, 3-, and 5-year overall survival rates after RFA of stage I NSCLC were 78% to 100%, 53% to 86%, 36% to 88%, and 25% to 61%, respectively. The median survival time ranged from 29 to 67 months. The 1-, 2-, and 3-year cancer-specific survival rates after RFA of stage I NSCLC were 89% to 100%, 92% to 93%, and 59% to 88%, respectively. RFA has a higher local failure rate than sublobar resection and stereotactic body radiation therapy (SBRT). Therefore, RFA may currently be reserved for early-stage NSCLC patients who are unfit for sublobar resection or SBRT. Various technologies are being developed to improve clinical outcomes of RFA for early-stage NSCLC. Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, and Susumu Kanazawa Copyright © 2014 Takao Hiraki et al. All rights reserved. Impact of Hemodialysis on Dyspnea and Lung Function in End Stage Kidney Disease Patients Thu, 08 May 2014 15:32:06 +0000 Background. Respiratory symptoms are usually underestimated in patients with chronic kidney disease undergoing maintenance hemodialysis. Therefore, we set out to investigate the prevalence of patients chronic dyspnea and the relationship of the symptom to lung function indices. Methods. Twenty-five clinically stable hemodialysis patients were included. The mMRC dyspnea scale was applied before and after hemodialysis. Spirometry, single breath nitrogen test, arterial blood gases, static maximum inspiratory () and expiratory () muscle pressures, and mouth occlusion pressure () were also measured. Results. Despite normal spirometry, all patients () reported mild to moderate degree of chronic dyspnea pre which was reduced after hemodialysis. The sole predictor of () mMRC was the () (). The was reduced before and correlated with the duration of hemodialysis (), whilst after the session it was significantly increased (). Finally () weight was correlated with the () () and with the () CV (). Conclusion. We conclude that dyspnea is the major symptom among the CKD patients that improves after hemodialysis. The neuromechanical dissociation observed probably is one of the major pathophysiologic mechanisms of dyspnea. Anastasios F. Palamidas, Sofia-Antiopi Gennimata, Foteini Karakontaki, Georgios Kaltsakas, Ioannis Papantoniou, Antonia Koutsoukou, Joseph Milic-Emili, Demetrios V. Vlahakos, and Nikolaos G. Koulouris Copyright © 2014 Anastasios F. Palamidas et al. All rights reserved. Application of Proteomics and Peptidomics to COPD Mon, 05 May 2014 07:32:44 +0000 Chronic obstructive pulmonary disease (COPD) is a complex disorder involving both airways and lung parenchyma, usually associated with progressive and poorly reversible airflow limitation. In order to better characterize the phenotypic heterogeneity and the prognosis of patients with COPD, there is currently an urgent need for discovery and validation of reliable disease biomarkers. Within this context, proteomic and peptidomic techniques are emerging as very valuable tools that can be applied to both systemic and pulmonary samples, including peripheral blood, induced sputum, exhaled breath condensate, bronchoalveolar lavage fluid, and lung tissues. Identification of COPD biomarkers by means of proteomic and peptidomic approaches can thus also lead to discovery of new molecular targets potentially useful to improve and personalize the therapeutic management of this widespread respiratory disease. Girolamo Pelaia, Rosa Terracciano, Alessandro Vatrella, Luca Gallelli, Maria Teresa Busceti, Cecilia Calabrese, Cristiana Stellato, Rocco Savino, and Rosario Maselli Copyright © 2014 Girolamo Pelaia et al. All rights reserved. Circulating Conventional and Plasmacytoid Dendritic Cell Subsets Display Distinct Kinetics during In Vivo Repeated Allergen Skin Challenges in Atopic Subjects Mon, 28 Apr 2014 13:45:39 +0000 Upon allergen challenge, DC subsets are recruited to target sites under the influence of chemotactic agents; however, details pertinent to their trafficking remain largely unknown. We investigated the kinetic profiles of blood and skin-infiltrating DC subsets in twelve atopic subjects receiving six weekly intradermal allergen and diluent injections. The role of activin-A, a cytokine induced in allergic and tissue repair processes, on the chemotactic profiles of DC subsets was also examined. Plasmacytoid (pDCs) and conventional DCs (cDCs) were evaluated at various time-points in the blood and skin. In situ activin-A expression was assessed in the skin and its effects on chemokine receptor expression of isolated cDCs were investigated. Blood pDCs were reduced 1 h after challenge, while cDCs decreased gradually within 24 h. Skin cDCs increased significantly 24 h after the first challenge, inversely correlating with blood cDCs. Activin-A in the skin increased 24 h after the first allergen challenge and correlated with infiltrating cDCs. Activin-A increased the CCR10/CCR4 expression ratio in cultured human cDCs. DC subsets demonstrate distinct kinetic profiles in the blood and skin especially during acute allergic inflammation, pointing to disparate roles depending on each phase of the inflammatory response. The effects of activin-A on modulating the chemotactic profile of cDCs suggest it may be a plausible therapeutic target for allergic diseases. Stelios Vittorakis, Konstantinos Samitas, Sofia Tousa, Eleftherios Zervas, Maria Aggelakopoulou, Maria Semitekolou, Vily Panoutsakopoulou, Georgina Xanthou, and Mina Gaga Copyright © 2014 Stelios Vittorakis et al. All rights reserved. Comorbidities in Chronic Obstructive Pulmonary Disease from Assessment to Treatment Wed, 02 Apr 2014 14:03:42 +0000 Enrico M. Clini, Piera Boschetto, Mitja Lainscak, and Wim Janssens Copyright © 2014 Enrico M. Clini et al. All rights reserved. Musculoskeletal Disorders in Chronic Obstructive Pulmonary Disease Tue, 25 Mar 2014 09:38:27 +0000 Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by airway obstruction and inflammation but also accompanied by several extrapulmonary consequences, such as skeletal muscle weakness and osteoporosis. Skeletal muscle weakness is of major concern, since it leads to poor functional capacity, impaired health status, increased healthcare utilization, and even mortality, independently of lung function. Osteoporosis leads to fractures and is associated with increased mortality, functional decline, loss of quality of life, and need for institutionalization. Therefore, the presence of the combination of these comorbidities will have a negative impact on daily life in patients with COPD. In this review, we will focus on these two comorbidities, their prevalence in COPD, combined risk factors, and pathogenesis. We will try to prove the clustering of these comorbidities and discuss possible preventive or therapeutic strategies. Nele Cielen, Karen Maes, and Ghislaine Gayan-Ramirez Copyright © 2014 Nele Cielen et al. All rights reserved. COgnitive-Pulmonary Disease Sun, 16 Mar 2014 12:14:30 +0000 Over the past few decades, chronic obstructive lung disease (COPD) has been considered a disease of the lungs, often caused by smoking. Nowadays, COPD is regarded as a systemic disease. Both physical effects and effects on brains, including impaired psychological and cognitive functioning, have been demonstrated. Patients with COPD may have cognitive impairment, either globally or in single cognitive domains, such as information processing, attention and concentration, memory, executive functioning, and self-control. Possible causes are hypoxemia, hypercapnia, exacerbations, and decreased physical activity. Cognitive impairment in these patients may be related to structural brain abnormalities, such as gray-matter pathologic changes and the loss of white matter integrity which can be induced by smoking. Cognitive impairment can have a negative impact on health and daily life and may be associated with widespread consequences for disease management programs. It is important to assess cognitive functioning in patients with COPD in order to optimize patient-oriented treatment and to reduce personal discomfort, hospital admissions, and mortality. This paper will summarize the current knowledge about cognitive impairment as extrapulmonary feature of COPD. Hereby, the impact of smoking on cognitive functioning and the impact of cognitive impairment on smoking behaviour will be examined. Fiona A. H. M. Cleutjens, Daisy J. A. Janssen, Rudolf W. H. M. Ponds, Jeanette B. Dijkstra, and Emiel F. M. Wouters Copyright © 2014 Fiona A. H. M. Cleutjens et al. All rights reserved. Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Cardiovascular Links Sun, 02 Mar 2014 13:32:27 +0000 Chronic obstructive pulmonary disease (COPD) is a chronic, progressive lung disease resulting from exposure to cigarette smoke, noxious gases, particulate matter, and air pollutants. COPD is exacerbated by acute inflammatory insults such as lung infections (viral and bacterial) and air pollutants which further accelerate the steady decline in lung function. The chronic inflammatory process in the lung contributes to the extrapulmonary manifestations of COPD which are predominantly cardiovascular in nature. Here we review the significant burden of cardiovascular disease in COPD and discuss the clinical and pathological links between acute exacerbations of COPD and cardiovascular disease. Cheryl R. Laratta and Stephan van Eeden Copyright © 2014 Cheryl R. Laratta and Stephan van Eeden. All rights reserved. A Cohort Study on Self-Reported Respiratory Symptoms of Toner-Handling Workers: Cross-Sectional and Longitudinal Analysis from 2003 to 2008 Thu, 27 Feb 2014 16:28:07 +0000 This study examines the relationship between toner-handling work and its health effects on self-reported respiratory symptoms. The subjects were 1,504 male workers in a Japanese toner and photocopier manufacturing company. Personal exposure measurement, pulmonary function tests, chest X-ray examination, measurement of biomarkers, and a questionnaire about self-reported respiratory symptoms were performed annually. This study discusses the questionnaire results. We found that the toner-handling group showed significantly higher prevalence of breathlessness than the never-toner-handling group. The significant reduction of pulmonary function and fibrosis change in the chest X-ray examination associated with breathlessness were not observed. However the morbidity of asthma was higher compared to the Japanese population in both of the toner-handling group and the never-toner handling group, the effect of toner exposure was not clarified. Nevertheless, while the toner exposure levels in the current well-controlled working environment may be sufficiently low to prevent adverse health effects, further studies are needed to assess the more long-term latent health effects of toner exposure. Hiroko Kitamura, Niina Terunuma, Shizuka Kurosaki, Koichi Hata, Masashi Masuda, Takeshi Kochi, Nobuaki Yanagi, Tadashi Murase, Akira Ogami, and Toshiaki Higashi Copyright © 2014 Hiroko Kitamura et al. All rights reserved. Exhaled Nitric Oxide as a Biomarker in COPD and Related Comorbidities Thu, 27 Feb 2014 10:56:27 +0000 Chronic Obstructive Pulmonary Disease (COPD) is defined as a disease characterized by persistent, progressive airflow limitation. Recent studies have underlined that COPD is correlated to many systemic manifestations, probably due to an underlying pattern of systemic inflammation. In COPD fractional exhaled Nitric Oxide (FeNO) levels are related to smoking habits and disease severity, showing a positive relationship with respiratory functional parameters. Moreover FeNO is increased in patients with COPD exacerbation, compared with stable ones. In alpha-1 antitrypsin deficiency, a possible cause of COPD, FeNO levels may be monitored to early detect a disease progression. FeNO measurements may be useful in clinical setting to identify the level of airway inflammation, per se and in relation to comorbidities, such as pulmonary arterial hypertension and cardiovascular diseases, either in basal conditions or during treatment. Finally, some systemic inflammatory diseases, such as psoriasis, have been associated with higher FeNO levels and potentially with an increased risk of developing COPD. In these systemic inflammatory diseases, FeNO monitoring may be a useful biomarker for early diagnosis of COPD development. Mario Malerba, Alessandro Radaeli, Alessia Olivini, Giovanni Damiani, Beatrice Ragnoli, Paolo Montuschi, and Fabio L. M. Ricciardolo Copyright © 2014 Mario Malerba et al. All rights reserved. Pulmonary Rehabilitation: The Reference Therapy for Undernourished Patients with Chronic Obstructive Pulmonary Disease Wed, 19 Feb 2014 16:21:41 +0000 Chronic obstructive pulmonary disease (COPD) combines the deleterious effects of chronic hypoxia, chronic inflammation, insulin-resistance, increased energy expenditure, muscle wasting, and exercise deconditioning. As for other chronic disorders, loss of fat-free mass decreased survival. The preservation of muscle mass and function, through the protection of the mitochondrial oxidative metabolism, is an important challenge in the management of COPD patients. As the prevalence of the disease is increasing and the medical advances make COPD patients live longer, the prevalence of COPD-associated nutritional disorders is expected to increase in future decades. Androgenopenia is observed in 40% of COPD patients. Due to the stimulating effects of androgens on muscle anabolism, androgenopenia favors loss of muscle mass. Studies have shown that androgen substitution could improve muscle mass in COPD patients, but alone, was insufficient to improve lung function. Two multicentric randomized clinical trials have shown that the association of androgen therapy with physical exercise and oral nutritional supplements containing omega-3 polyinsaturated fatty acids, during at least three months, is associated with an improved clinical outcome and survival. These approaches are optimized in the field of pulmonary rehabilitation which is the reference therapy of COPD-associated undernutrition. Nikolaos Samaras, Dimitrios Samaras, Arnaud Chambellan, Claude Pichard, and Ronan Thibault Copyright © 2014 Nikolaos Samaras et al. All rights reserved. Alcohol Induced Mitochondrial Oxidative Stress and Alveolar Macrophage Dysfunction Wed, 19 Feb 2014 11:37:05 +0000 An alcohol use disorder increases the risk of invasive and antimicrobial resistant community-acquired pneumonia and tuberculosis. Since the alveolar macrophage (AM) orchestrates the immune response in the alveolar space, understanding the underlying mechanisms by which alcohol suppresses AM phagocytosis is critical to improving clinical outcomes. In the alveolar space, chronic alcohol ingestion causes severe oxidative stress and depletes antioxidants which are critical for AM function. The mitochondrion is important in maintaining cellular redox balance and providing the ATP critical for phagocytosis. The focus of this study was to understand how alcohol triggers mitochondrial reactive oxygen species (ROS), stimulates cellular oxidative stress, and induces AM dysfunction. The current study also investigated the capacity of the mitochondrial targeted antioxidant, mitoTEMPOL (mitoT), in modulating mitochondrial oxidative stress, and AM dysfunction. Using in vitro ethanol exposure and AMs from ethanol-fed mice, ethanol promoted mitochondrial dysfunction including increased mitochondrial ROS, decreased mitochondrial membrane potential, and decreased ATP. Treatment with mitoT reversed these effects. Ethanol-induced decreases in phagocytosis and cell viability were also attenuated with mitoT. Therefore, antioxidants targeted to the mitochondria have the potential to ameliorate ethanol-induced mitochondrial oxidative stress and subsequent decreases in AM phagocytosis and cell viability. Yan Liang, Frank L. Harris, and Lou Ann S. Brown Copyright © 2014 Yan Liang et al. All rights reserved. Contribution of Psychological Factors in Dropping out from Chronic Obstructive Pulmonary Disease Rehabilitation Programs Thu, 13 Feb 2014 14:03:45 +0000 Significant positive effects, particularly on psychological state in patients who completed the follow-up pulmonary rehabilitation programs, are indicated by a large number of studies. Yet, a remarkable proportion of selected patients drop out from these programs. In this study, we investigated existing differences on psychological variables among COPD patients who complete and those who drop out from pulmonary rehabilitation programs. The study included 144 patients, 43 (29.9%) of whom did not complete the program. SCL-90 was used for the assessment of psychological symptoms. On the SCL-90-R scale 55.6% of patients had abnormal findings. Patients who discontinued the program had higher rates of depression and somatization compared to those who completed it. Regarding the psychopathology scales of SCL-90R, we found that patients who discontinued the program showed higher levels of psychopathology on the scales of somatization, depression, paranoid ideation, and psychotism compared to those who completed the program. The final regression model showed that patients with low educational status and psychotism were more likely to leave the program. In conclusion, psychopathology contributes to patients dropping out from a COPD rehabilitation program; thus, psychological assessment prior to inclusion in rehabilitation programs may reduce dropouts. Athanasios Tselebis, Epaminondas Kosmas, Dionisios Bratis, Argiro Pachi, Ioannis Ilias, Maria Harikiopoulou, Elpida Theodorakopoulou, Konstantinos Velentzas, Silvia Dumitru, Georgios Moussas, Nikolaos Siafakas, and Nikolaos Tzanakis Copyright © 2014 Athanasios Tselebis et al. All rights reserved. Identification of Clinical Phenotypes Using Cluster Analyses in COPD Patients with Multiple Comorbidities Mon, 10 Feb 2014 13:42:10 +0000 Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, the severity of which is assessed using forced expiratory volume in 1 sec (FEV1, % predicted). Cohort studies have confirmed that COPD patients with similar levels of airflow limitation showed marked heterogeneity in clinical manifestations and outcomes. Chronic coexisting diseases, also called comorbidities, are highly prevalent in COPD patients and likely contribute to this heterogeneity. In recent years, investigators have used innovative statistical methods (e.g., cluster analyses) to examine the hypothesis that subgroups of COPD patients sharing clinically relevant characteristics (phenotypes) can be identified. The objectives of the present paper are to review recent studies that have used cluster analyses for defining phenotypes in observational cohorts of COPD patients. Strengths and weaknesses of these statistical approaches are briefly described. Description of the phenotypes that were reasonably reproducible across studies and received prospective validation in at least one study is provided, with a special focus on differences in age and comorbidities (including cardiovascular diseases). Finally, gaps in current knowledge are described, leading to proposals for future studies. Pierre-Régis Burgel, Jean-Louis Paillasseur, and Nicolas Roche Copyright © 2014 Pierre-Régis Burgel et al. All rights reserved. Determinants of Noninvasive Ventilation Outcomes during an Episode of Acute Hypercapnic Respiratory Failure in Chronic Obstructive Pulmonary Disease: The Effects of Comorbidities and Causes of Respiratory Failure Sun, 19 Jan 2014 09:53:53 +0000 Objectives. To investigate the effect of the cause of acute respiratory failure and the role of comorbidities both acute and chronic on the outcome of COPD patients admitted to Respiratory Intensive Care Unit (RICU) with acute respiratory failure and treated with NIV. Design. Observational prospective study. Patients and Methods. 176 COPD patients consecutively admitted to our RICU over a period of 3 years and treated with NIV were evaluated. In all patients demographic, clinical, and functional parameters were recorded including the cause of acute respiratory failure, SAPS II score, Charlson comorbidity index, and further comorbidities not listed in the Charlson index. NIV success was defined as clinical improvement leading to discharge to regular ward, while exitus or need for endotracheal intubation was considered failure. Results. NIV outcome was successful in 134 patients while 42 underwent failure. Univariate analysis showed significantly higher SAP II score, Charlson index, prevalence of pneumonia, and lower serum albumin level in the failure group. Multivariate analysis confirmed a significant predictive value for pneumonia and albumin. Conclusions. The most important determinants of NIV outcome in COPD patients are the presence of pneumonia and the level of serum albumin as an indicator of the patient nutritional status. Angela Maria Grazia Pacilli, Ilaria Valentini, Paolo Carbonara, Antonio Marchetti, and Stefano Nava Copyright © 2014 Angela Maria Grazia Pacilli et al. All rights reserved. Altered Pulmonary Lymphatic Development in Infants with Chronic Lung Disease Thu, 02 Jan 2014 15:52:50 +0000 Pulmonary lymphatic development in chronic lung disease (CLD) has not been investigated, and anatomy of lymphatics in human infant lungs is not well defined. Hypothesis. Pulmonary lymphatic hypoplasia is present in CLD. Method. Autopsy lung tissues of eighteen subjects gestational ages 22 to 40 weeks with and without history of respiratory morbidity were stained with monoclonal antipodoplanin and reviewed under light microscopy. Percentage of parenchyma podoplanin stained at the acinar level was determined using computerized image analysis; 9 CLD and 4 control subjects gestational ages 27 to 36 weeks were suitable for the analysis. Results. Distinct, lymphatic-specific staining with respect to other vascular structures was appreciated in all gestations. Infants with and without respiratory morbidity had comparable lymphatic distribution which extended to the alveolar ductal level. Podoplanin staining per parenchyma was increased and statistically significant in the CLD group versus controls at the alveolar ductal level (0.06% ± 0.02% versus 0.04% ± 0.01%, 95% CI −0.04% to −0.002%, ). Conclusion. Contrary to our hypothesis, the findings show that there is an increase in alveolar lymphatics in CLD. It is suggested that the findings, by expanding current knowledge of CLD pathology, may offer insight into the development of more effective therapies to tackle CLD. Emily M. McNellis, Sherry M. Mabry, Eugenio Taboada, and Ikechukwu I. Ekekezie Copyright © 2014 Emily M. McNellis et al. All rights reserved. The Influence of Comorbidities on Outcomes of Pulmonary Rehabilitation Programs in Patients with COPD: A Systematic Review Thu, 26 Dec 2013 10:20:01 +0000 Introduction. Chronic obstructive pulmonary disease (COPD) is associated with comorbidities such as cardiovascular disease, metabolic disease, osteoporosis, and anxiety and/or depression. Although pulmonary rehabilitation programs are proven to be beneficial in patients with COPD, it is unclear whether comorbidities influence pulmonary rehabilitation outcomes. The aim of the present review was to investigate to what extent the presence of comorbidities can affect pulmonary rehabilitation outcomes. Methods. The systematic literature search (Pubmed, EMBASE, and PEDro) resulted in 4 articles meeting the inclusion criteria. The odds ratios (95% confidence intervals) of the logistic regression analyses, with comorbidities as independent variables and pulmonary rehabilitation outcomes (dyspnea, functional exercise capacity, and quality of life) as dependent variables, were used for data extraction. Results. Patients with anxiety and/or depression less likely improve in dyspnea. Osteoporosis is associated with less improvements in functional exercise capacity, while cardiovascular disease does not seem to negatively impact on this outcome. Patients with cardiovascular comorbidity will experience less positive changes in quality of life. Conclusion. Evidence from literature suggests that comorbidities can have a negative influence on pulmonary rehabilitation outcomes. Screening for comorbidities in pulmonary rehabilitation settings seems useful to readdress the right patients for individually tailored pulmonary rehabilitation. Miek Hornikx, Hans Van Remoortel, Heleen Demeyer, Carlos Augusto Marcal Camillo, Marc Decramer, Wim Janssens, and Thierry Troosters Copyright © 2013 Miek Hornikx et al. All rights reserved. Role of Redox Signaling in Neuroinflammation and Neurodegenerative Diseases Tue, 24 Dec 2013 09:16:38 +0000 Reactive oxygen species (ROS), a redox signal, are produced by various enzymatic reactions and chemical processes, which are essential for many physiological functions and act as second messengers. However, accumulating evidence has implicated the pathogenesis of several human diseases including neurodegenerative disorders related to increased oxidative stress. Under pathological conditions, increasing ROS production can regulate the expression of diverse inflammatory mediators during brain injury. Elevated levels of several proinflammatory factors including cytokines, peptides, pathogenic structures, and peroxidants in the central nervous system (CNS) have been detected in patients with neurodegenerative diseases such as Alzheimer’s disease (AD). These proinflammatory factors act as potent stimuli in brain inflammation through upregulation of diverse inflammatory genes, including matrix metalloproteinases (MMPs), cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), and adhesion molecules. To date, the intracellular signaling mechanisms underlying the expression of target proteins regulated by these factors are elusive. In this review, we discuss the mechanisms underlying the intracellular signaling pathways, especially ROS, involved in the expression of several inflammatory proteins induced by proinflammatory factors in brain resident cells. Understanding redox signaling transduction mechanisms involved in the expression of target proteins and genes may provide useful therapeutic strategies for brain injury, inflammation, and neurodegenerative diseases. Hsi-Lung Hsieh and Chuen-Mao Yang Copyright © 2013 Hsi-Lung Hsieh and Chuen-Mao Yang. All rights reserved. Six-Minute Walking Distance Improvement after Pulmonary Rehabilitation Is Associated with Baseline Lung Function in Complex COPD Patients: A Retrospective Study Wed, 18 Dec 2013 14:43:57 +0000 Introduction. Conflicting results have been so far reported about baseline lung function, as predicting factor of pulmonary rehabilitation (PR) efficacy. Aim. To ascertain whether or not baseline lung function could predict a benefit in terms of a significant change in 6-min walk test (6MWT) after PR. Methods. Seventy-five stable moderate-to-severe COPD inpatients with comorbidities (complex COPD), allocated to a three-week PR program, were retrospectively evaluated. Pulmonary function, 6MWT, dyspnea (BDI/TDI), and quality of life (EQ-VAS) were assessed before and after PR program. The patients were divided into two groups depending on the change in 6MWT (responders 30 m and nonresponders 30 m). Logistic regression analysis was used. Results. After PR, 6MWT performance all outcome measures significantly improved (). Compared to nonresponders (), the responders () had lower values in baseline lung function (). Logistic regression analysis showed that FEV1    50% pred and TL, CO   50% pred were independent predictors of PR efficacy. Conclusions. Our study shows that in stable moderate-to-severe complex COPD inpatients, baseline lung function may predict the response to PR in terms of 6MWT. We also found that complex COPD patients with poor lung function get more benefit from PR. Andrea Zanini, Alfredo Chetta, Federico Gumiero, Sabrina Della Patrona, Silvia Casale, Elisabetta Zampogna, Marina Aiello, and Antonio Spanevello Copyright © 2013 Andrea Zanini et al. All rights reserved. Cardiovascular Function in Pulmonary Emphysema Tue, 03 Dec 2013 18:01:39 +0000 Chronic obstructive pulmonary disease (COPD) and chronic cardiovascular disease, such as coronary artery disease, congestive heart failure, and cardiac arrhythmias, have a strong influence on each other, and systemic inflammation has been considered as the main linkage between them. On the other hand, airflow limitation may markedly affect lung mechanics in terms of static and dynamic hyperinflation, especially in pulmonary emphysema, and they can in turn influence cardiac performance as well. Skeletal mass depletion, which is a common feature in COPD especially in pulmonary emphysema patients, may have also a role in cardiovascular function of these patients, irrespective of lung damage. We reviewed the emerging evidence that highlights the role of lung mechanics and muscle mass impairment on ventricular volumes, stroke volume, and stroke work at rest and on exercise in the presence of pulmonary emphysema. Patients with emphysema may differ among COPD population even in terms of cardiovascular function. Dina Visca, Marina Aiello, and Alfredo Chetta Copyright © 2013 Dina Visca et al. All rights reserved. Immune Responses following Stereotactic Body Radiotherapy for Stage I Primary Lung Cancer Sun, 10 Nov 2013 09:21:25 +0000 Purpose. Immune responses following stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) were examined from the point of view of lymphocyte subset counts and natural killer cell activity (NKA). Patients and Methods. Peripheral blood samples were collected from 62 patients at 4 time points between pretreatment and 4 weeks post-treatment for analysis of the change of total lymphocyte counts (TLC) and lymphocyte subset counts of CD3+, CD4+, CD8+, CD19+, CD56+, and NKA. In addition, the changes of lymphocyte subset counts were compared between patients with or without relapse. Further, the correlations between SBRT-related parameters and immune response were analyzed for the purpose of revealing the mechanisms of the immune response. Results. All lymphocyte subset counts and NKA at post-treatment and 1 week post-treatment were significantly lower than pre-treatment (). No significant differences in the changes of lymphocyte subset counts were observed among patients with or without relapse. The volume of the vertebral body receiving radiation doses of 3 Gy or more (VV3) significantly correlated with the changes of nearly all lymphocyte subset counts. Conclusions. SBRT for stage I NSCLC induced significant immune suppression, and the decrease of lymphocyte subset counts may be associated with exposure of the vertebral bone marrow. Yoshiyasu Maehata, Hiroshi Onishi, Kengo Kuriyama, Shinichi Aoki, Masayuki Araya, Ryo Saito, Licht Tominaga, Mitsuhiko Oguri, and Tsutomu Araki Copyright © 2013 Yoshiyasu Maehata et al. All rights reserved. Over, and Underexpression of Endothelin 1 and TGF-Beta Family Ligands and Receptors in Lung Tissue of Broilers with Pulmonary Hypertension Mon, 28 Oct 2013 13:31:07 +0000 Transforming growth factor beta (TGFβ) is a family of genes that play a key role in mediating tissue remodeling in various forms of acute and chronic lung disease. In order to assess their role on pulmonary hypertension in broilers, we determined mRNA expression of genes of the TGFβ family and endothelin 1 in lung samples from 4-week-old chickens raised either under normal or cold temperature conditions. Both in control and cold-treated groups of broilers, endothelin 1 mRNA expression levels in lungs from ascitic chickens were higher than levels from healthy birds (), whereas levels in animals with cardiac failure were intermediate. Conversely, TGFβ2 and TGFβ3 gene expression in lungs were higher in healthy animals than in ascitic animals in both groups (). TGFβ1, TβRI, and TβRII mRNA gene expression among healthy, ascitic, and chickens with cardiac failure showed no differences (). BAMBI mRNA gene expression was lowest in birds with ascites only in the control group as compared with the values from healthy birds (). Norma Dominguez-Avila, Gabriel Ruiz-Castañeda, Javier González-Ramírez, Nora Fernandez-Jaramillo, Jorge Escoto, Fausto Sánchez-Muñoz, Ricardo Marquez-Velasco, Rafael Bojalil, Román Espinosa-Cervantes, and Fausto Sánchez Copyright © 2013 Norma Dominguez-Avila et al. All rights reserved. Risk Prediction Models for Mortality in Community-Acquired Pneumonia: A Systematic Review Mon, 21 Oct 2013 15:48:45 +0000 Background. Several models have been developed to predict the risk of mortality in community-acquired pneumonia (CAP). This study aims to systematically identify and evaluate the performance of published risk prediction models for CAP. Methods. We searched MEDLINE, EMBASE, and Cochrane library in November 2011 for initial derivation and validation studies for models which predict pneumonia mortality. We aimed to present the comparative usefulness of their mortality prediction. Results. We identified 20 different published risk prediction models for mortality in CAP. Four models relied on clinical variables that could be assessed in community settings, with the two validated models BTS1 and CRB-65 showing fairly similar balanced accuracy levels (0.77 and 0.72, resp.), while CRB-65 had AUROC of 0.78. Nine models required laboratory tests in addition to clinical variables, and the best performance levels amongst the validated models were those of CURB and CURB-65 (balanced accuracy 0.73 and 0.71, resp.), with CURB-65 having an AUROC of 0.79. The PSI (AUROC 0.82) was the only validated model with good discriminative ability among the four that relied on clinical, laboratorial, and radiological variables. Conclusions. There is no convincing evidence that other risk prediction models improve upon the well-established CURB-65 and PSI models. Chun Shing Kwok, Yoon K. Loke, Kenneth Woo, and Phyo Kyaw Myint Copyright © 2013 Chun Shing Kwok et al. All rights reserved. Neonatal Hyperoxic Exposure Persistently Alters Lung Secretoglobins and Annexin A1 Thu, 26 Sep 2013 09:02:01 +0000 Altered functions of the lung epithelial surface likely contribute to the respiratory morbidities in infants with bronchopulmonary dysplasia (BPD). Infants with BPD exhibit decreased expressions of secretoglobins (SCGBs), including Clara cell secretory protein (CCSP). Expression of lung SCGB and annexin A1 (ANXA1) is persistently altered in CCSP knockout mice suggesting that CCSP indirectly influences innate immune responses. The present studies tested the hypothesis that neonatal hyperoxic exposure induces deficits in CCSP expression that are associated with persistent alterations in lung SCGB and ANXA1 expression. Newborn C3H/HeN mice were exposed to room air (RA) or 85% O2 from birth and were sacrificed at 14 d or returned to RA for 14 d. Neonatal hyperoxia followed by RA recovery was associated with decreased lung CCSP and SCGB3A1 protein but not mRNA expression. Hyperoxia-induced alterations in the charge characteristics of ANXA1 were unchanged by RA recovery and were associated with elevated lung macrophage numbers. These findings support a model in which hyperoxia-induced alterations in Clara cell function influence lung innate immune function through effects on immunomodulatory proteins. Studies to determine the mechanism(s) by which CCSP alterations affect SCGBs, ANXA1, and innate immune responses in BPD are warranted. Thomas M. Raffay, Morgan L. Locy, Cynthia L. Hill, Nik S. Jindal, Lynette K. Rogers, Stephen E. Welty, and Trent E. Tipple Copyright © 2013 Thomas M. Raffay et al. All rights reserved. Breath Tests in Respiratory and Critical Care Medicine: From Research to Practice in Current Perspectives Wed, 18 Sep 2013 17:37:28 +0000 Today, exhaled nitric oxide has been studied the most, and most researches have now focusd on asthma. More than a thousand different volatile organic compounds have been observed in low concentrations in normal human breath. Alkanes and methylalkanes, the majority of breath volatile organic compounds, have been increasingly used by physicians as a novel method to diagnose many diseases without discomforts of invasive procedures. None of the individual exhaled volatile organic compound alone is specific for disease. Exhaled breath analysis techniques may be available to diagnose and monitor the diseases in home setting when their sensitivity and specificity are improved in the future. Attapon Cheepsattayakorn and Ruangrong Cheepsattayakorn Copyright © 2013 Attapon Cheepsattayakorn and Ruangrong Cheepsattayakorn. All rights reserved. Respiratory Management in the Patient with Spinal Cord Injury Mon, 09 Sep 2013 09:29:05 +0000 Spinal cord injuries (SCIs) often lead to impairment of the respiratory system and, consequently, restrictive respiratory changes. Paresis or paralysis of the respiratory muscles can lead to respiratory insufficiency, which is dependent on the level and completeness of the injury. Respiratory complications include hypoventilation, a reduction in surfactant production, mucus plugging, atelectasis, and pneumonia. Vital capacity (VC) is an indicator of overall pulmonary function; patients with severely impaired VC may require assisted ventilation. It is best to proceed with intubation under controlled circumstances rather than waiting until the condition becomes an emergency. Mechanical ventilation can adversely affect the structure and function of the diaphragm. Early tracheostomy following short orotracheal intubation is probably beneficial in selected patients. Weaning should start as soon as possible, and the best modality is progressive ventilator-free breathing (PVFB). Appropriate candidates can sometimes be freed from mechanical ventilation by electrical stimulation. Respiratory muscle training regimens may improve patients’ inspiratory function following a SCI. Rita Galeiras Vázquez, Pedro Rascado Sedes, Mónica Mourelo Fariña, Antonio Montoto Marqués, and M. Elena Ferreiro Velasco Copyright © 2013 Rita Galeiras Vázquez et al. All rights reserved. The Effect of Silver Nitrate Pleurodesis after a Failed Thoracoscopic Talc Poudrage Sun, 01 Sep 2013 12:04:11 +0000 Background. Chemical pleurodesis is the procedure of choice in the management of recurrent malignant pleural effusions (MPE). Talc is probably the most effective sclerosant, with a success rate of 80%. The aim of this study is to demonstrate the effectiveness of silver nitrate solution (SNS) pleurodesis after an unsuccessful thoracoscopic talc poudrage. Methods. Between 2011 and 2013 one hundred and nine patients with unilateral MPE underwent thoracoscopic talc poudrage. Seventeen patients who did not obtain a successful pleurodesis via thoracoscopic procedure were considered for an SNS slurry. The pleural injectate consisted of 100 mL 1% SNS with 10 mL of lidocaine (100 mg/5 mL). The SNS procedure was undertaken once and repeated with the same dose in 5 patients. Results. The duration of follow-up period was 30 days. Subjective pain was low and the same before and after SNS procedure ( value = NS). The mean daily fluid drainage was statistically different () comparing values before ( mL) and after SNS procedure ( mL). After 30 days from SNS procedure recurrence of pleural effusion was observed in 2 patients (11%). Conclusions. The present study demonstrates that SNS is an effective agent for producing pleurodesis after a failed thoracoscopic talc poudrage. Cecilia Menna, Claudio Andreetti, Mohsen Ibrahim, Giulio Maurizi, Camilla Poggi, Rocco Barile, Francesco Cassiano, and Erino A. Rendina Copyright © 2013 Cecilia Menna et al. All rights reserved. Cryobiopsy: Should This Be Used in Place of Endobronchial Forceps Biopsies? Tue, 27 Aug 2013 11:44:57 +0000 Forceps biopsies of airway lesions have variable yields. The yield increases when combining techniques in order to collect more material. With the use of cryotherapy probes (cryobiopsy) larger specimens can be obtained, resulting in an increase in the diagnostic yield. However, the utility and safety of cryobiopsy with all types of lesions, including flat mucosal lesions, is not established. Aims. Demonstrate the utility/safety of cryobiopsy versus forceps biopsy to sample exophytic and flat airway lesions. Settings and Design. Teaching hospital-based retrospective analysis. Methods. Retrospective analysis of patients undergoing cryobiopsies (singly or combined with forceps biopsies) from August 2008 through August 2010. Statistical Analysis. Wilcoxon signed-rank test. Results. The comparative analysis of 22 patients with cryobiopsy and forceps biopsy of the same lesion showed the mean volumes of material obtained with cryobiopsy were significantly larger (0.696 cm3 versus 0.0373 cm3, ). Of 31 cryobiopsies performed, one had minor bleeding. Cryopbiopsy allowed sampling of exophytic and flat lesions that were located centrally or distally. Cryobiopsies were shown to be safe, free of artifact, and provided a diagnostic yield of 96.77%. Conclusions. Cryobiopsy allows safe sampling of exophytic and flat airway lesions, with larger specimens, excellent tissue preservation and high diagnostic accuracy. Edmundo R. Rubio, Susanti R. le, Ralph E. Whatley, and Michael B. Boyd Copyright © 2013 Edmundo R. Rubio et al. All rights reserved. The Usefulness of Confusion, Urea, Respiratory Rate, and Shock Index or Adjusted Shock Index Criteria in Predicting Combined Mortality and/or ICU Admission Compared to CURB-65 in Community-Acquired Pneumonia Tue, 20 Aug 2013 09:13:40 +0000 Background and Objectives. The study aims to assess the usefulness of age-independent criteria CURSI and temperature adjusted CURSI (CURASI) compared to CURB-65 in predicting community-acquired pneumonia (CAP) mortality. The criteria, CRSI and CRASI, were adapted for use in primary care and compared to CRB-65. Methods. A retrospective analysis of a prospectively identified cohort of community-acquired pneumonia inpatients was conducted. Outcomes were (1) mortality and (2) mortality and/or ICU admission within six weeks. Results. 95 patients (median age = 61 years) were included. All three criteria had similar sensitivity in predicting mortality alone, with CURB-65 having slightly higher specificity. When predicting mortality and/or intensive care admission, CURSI/CURASI showed higher sensitivity and slightly lower specificity. CRSI and CRASI had higher sensitivity and lower specificity when compared with CRB-65 for predicting both primary and secondary outcomes. Results for both analyses had P values >0.05. Conclusions. In a cohort of younger patients CURSI and adjusted CURSI perform at least as well as CURB-65, with a similar trend for CRSI and adjusted CRSI compared to CRB-65. Further studies are needed in different age groups and in primary and secondary care settings. James P. Curtain, Prasanna Sankaran, Ajay V. Kamath, and Phyo K. Myint Copyright © 2013 James P. Curtain et al. All rights reserved. Hypoxic Pulmonary Vasoconstriction in Humans Tue, 20 Aug 2013 08:32:57 +0000 Hypoxic pulmonary vasoconstriction is the elegant theory put forward more than six decades ago to explain regional variations in perfusion within the lung in certain animal species in response to localised restrictions in oxygenation. Although considerable progress has been made to describe the phenomenon at the macroscopic level and explain it at the microscopic level, we are far from a universal agreement about the process in humans. This review attempts to highlight some of the important evidence bases of hypoxic pulmonary vasoconstriction in humans and the significant gaps in our knowledge that would need bridging. Priyadharshanan Ariyaratnam, Mahmoud Loubani, and Alyn H. Morice Copyright © 2013 Priyadharshanan Ariyaratnam et al. All rights reserved. Bronchial Responsiveness in Patients with Restrictive Spirometry Sun, 18 Aug 2013 13:15:55 +0000 Background. Improvement in PFT after bronchodilators is characteristic of obstructive airway diseases such as COPD. However, improvement in patients with restrictive pattern is occasionally seen. We aim to determine the clinical significance of a bronchodilator responsive restrictive defect. Methods. Patients with restrictive spirometry and a bronchodilator study were identified at the University of Oklahoma and Oklahoma City VAMC between September 2003 and December 2009. Restriction was defined as a decreased FVC and FEV1, with normal FEV1/FVC. Responsiveness to bronchodilators was defined as an improvement in FEV1 and/or FVC of at least 12% and 200 mL. Patients with lung volume measurements had their clinical and radiographic records reviewed. Results. Twenty-one patients were included in the study. Most were current or ex-smokers, with most being on bronchodilators. The average FVC and FEV1 were and of the predicted, respectively. Most patients (66%) had a normal TLC, averaging of the predicted. RV, RV/TLC, and the TLC-VA values strongly suggested an obstructive defect. Conclusions. Reversible restrictive pattern on spirometry appears to be a variant of obstructive lung disease in which early airway closure results in air trapping and low FVC. In symptomatic patients, a therapeutic trial of bronchodilators may be beneficial. Jean I. Keddissi, Marwan K. Elya, Saif U. Farooq, Houssein A. Youness, Kellie R. Jones, Ahmed Awab, and Gary T. Kinasewitz Copyright © 2013 Jean I. Keddissi et al. All rights reserved. Erlotinib and Concurrent Chemoradiation in Pretreated NSCLC Patients: Radiobiological Basis and Clinical Results Sun, 04 Aug 2013 11:43:35 +0000 Aims. To establish feasibility of the combination of Erlotinib and concurrent chemoradiation in pre-treated patients with locally advanced or metastatic NSCLC. Materials and Methods. Data regarding 60 consecutive patients with NSCLC previously treated with chemotherapy alone were prospectically collected. All patients started Erlotinib concurrently with chemotherapy and radiation delivered to primary tumor. These data were retrospectively analyzed (observational study). Feasibility and toxicity were the primary endpoints, with response rate and progression being the secondary ones, while survival data are reported just as exploratory analysis. The EGFR mutational status was recorded in 32% of cases and it was always wild type. Results. Compliance to the combination protocol was good. Grade 3-4 esophagitis and acute lung toxicity occurred in 2% and 8% of patients, respectively. No progressive disease was recorded in the majority of cases (65%). Median OS and PFS were 23.3 and 4.7 months, respectively. Patients not responding to chemotherapy administered prior to chemoradiation achieved an objective response rate of 53.3% and complete response in 13.3% of cases. Conclusions. The addition of Erlotinib to chemoradiation in inoperable NSCLCs is feasible with interesting efficacy profile. These preliminary results warrant further investigation in patients with locally advanced nonmetastatic NSCLC with EGFR mutations. Sara Ramella, Antonio Maria Alberti, Eugenio Cammilluzzi, Michele Fiore, Edy Ippolito, Carlo Greco, Angelo Luca De Quarto, Sara Ramponi, Giovanni Apolone, Lucio Trodella, Alfredo Cesario, and Rolando Maria D’Angelillo Copyright © 2013 Sara Ramella et al. All rights reserved. Effect of Folic Acid and Vitamin on Pemetrexed Antifolate Chemotherapy in Nutrient Lung Cancer Cells Wed, 31 Jul 2013 09:39:05 +0000 Pemetrexed (MTA) is a multitargeted antifolate drug approved for lung cancer therapy. Clinically, supplementation with high doses of folic acid (FA) and vitamin B12 (VB12) lowers MTA cytotoxicities. An antagonistic effect of FA/VB12 on MTA efficacy has been proposed. However, patients who receive FA/VB12 show better tolerance to MTA with improved survival. The aims of this study are to investigate the modulation of FA and VB12 on MTA drug efficacy in human nonsmall cell lung cancer (NSCLC) cell lines. The sensitivities of cells, apoptosis, and MTA-regulated proteins were characterized to determine the possible effects of high doses of FA and VB12 on MTA efficacy. MTA has the lowest efficacy under 10% serum conditions. However, supplementation with FA and VB12 individually and additively reversed the insensitivity of NSCLC cells to MTA treatment with 10% serum. The enhanced sensitivities of cells following FA/VB12 treatment were correlated with increasing apoptosis and were specific to MTA but not to 5-fluorouracil (5-FU). Enhanced sensitivity was also associated with p expression level. Our results revealed no antagonistic effect of high doses of FA/VB12 on MTA efficacy in cancer cells grown in nutrient medium. Furthermore, these data may partially explain why supplementation of FA and VB12 resulted in better survival in MTA-treated patients. Tsung-Ying Yang, Gee-Chen Chang, Shih-Lan Hsu, Yi-Rou Huang, Ling-Yen Chiu, and Gwo-Tarng Sheu Copyright © 2013 Tsung-Ying Yang et al. All rights reserved. Association between Allergic Rhinitis and Asthma Control in Peruvian School Children: A Cross-Sectional Study Thu, 25 Jul 2013 14:47:11 +0000 Background. Asthma and allergic rhinitis are highly prevalent conditions that cause major illness worldwide. This study aimed to assess the association between allergic rhinitis and asthma control in Peruvian school children. Methods. A cross-sectional study was conducted among 256 children with asthma recruited in 5 schools from Lima and Callao cities. The outcome was asthma control assessed by the asthma control test. A score test for trend of odds was used to evaluate the association between allergic rhinitis severity and the prevalence of inadequate asthma control. A generalized linear regression model was used to estimate the adjusted prevalence ratios of inadequate asthma control. Results. Allergic rhinitis was present in 66.4% of the population with asthma. The trend analysis showed a positive association between allergic rhinitis and the probability of inadequate asthma control (). It was associated with an increased prevalence of inadequate asthma control, with adjusted prevalence ratios of 1.53 (95% confidence interval: 1.19−1.98). Conclusion. This study indicates that allergic rhinitis is associated with an inadequate level of asthma control, giving support to the recommendation of evaluating rhinitis to improve asthma control in children. Justo Padilla, Mónica Uceda, Otto Ziegler, Felipe Lindo, Eder Herrera-Pérez, and Luis Huicho Copyright © 2013 Justo Padilla et al. All rights reserved. Factors Associated within 28 Days In-Hospital Mortality of Patients with Acute Respiratory Distress Syndrome Wed, 26 Jun 2013 14:03:32 +0000 Objective. To determine the factors leading to in-hospital mortality within 28 days in hospitalized patients with ARDS. It was a prospective observational cohort study conducted in Intensive Care Unit of Aga Khan University Hospital Karachi from March to August 2011. Methodology. Data was collected from patients admitted in the intensive care unit on the basis of inclusion and exclusion criteria. The patients were followed daily for 28 days to record any in-hospital complications and the outcome of patients. Results. Total of 46 patients were included during this period out of which 56% (26) were males and 43% (20) were females. Mean age was 44 ± 19 years. There were 11 (23.9%) patients with age >65 and 35 (76%) had age <65 years. There were 21 (45.6%) patients with pulmonary ARDS and 25 (54.3%) had extrapulmonary ARDS. APACHE II score of >20 was present in 23 (50%) patients while the rest had score of <20. Regarding in-hospital complications, 23 (50%) patients developed sepsis, 31 (67.4%) had multiorgan failure, 14 (30%) had refractory shock, and 15 (32.6%) developed refractory hypoxemia. Out of 46 patients, 26 (56.5%) died within 28 days. On univariate analysis, high APACHE score, multiorgan failure, refractory shock, and refractory hypoxemia were main causes of death. Conclusion. ARDS is a syndrome of high mortality with mortality rate of 56.5% in this study. High APACHE, sepsis, multiorgan failure, refractory shock, and refractory hypoxemia are the leading causes of death in our patients. Nadia Sharif, Muhammad Irfan, Javaid Hussain, and Javaid Khan Copyright © 2013 Nadia Sharif et al. All rights reserved. Interleukin-13 +1923C/T Polymorphism Is Associated with Asthma Risk: A Meta-Analysis Tue, 11 Jun 2013 11:43:14 +0000 There are controversies on the association between interleukin-13 (IL-13) +1923C/T polymorphism (rs1295686) and the risk of asthma. We performed this study to assess the association by the method of meta-analysis. A systematic search current to October 16, 2012, was conducted using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) and identified ten studies comprising 13698 cases and 38209 controls. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. There was a significant association between IL-13 +1923C/T polymorphism and asthma risk in codominant model. When stratified by ethnicity, IL-13 +1923C/T polymorphism remained significantly associated with higher asthma risk in Asians and Caucasians. In the subgroup analysis by study quality, a significantly increased asthma risk was observed in high quality studies. Sensitivity analysis and cumulative analysis further strengthened the validity of the results. No publication bias was found in this meta-analysis. In conclusion, results from this meta-analysis suggested that IL-13 +1923C/T polymorphism was a risk factor of asthma. Yongan Liu, Tao Liu, Wei Nie, Guoxiang Lai, and Qingyu Xiu Copyright © 2013 Yongan Liu et al. All rights reserved. Increased Expression of Epidermal Growth Factor Receptor (EGF-R) in Patients with Different Forms of Lung Fibrosis Sun, 09 Jun 2013 10:55:11 +0000 Introduction. Emerging evidence supports the role of epidermal growth factor-receptor (EGFR) in fibrogenesis. The aim of our study was to investigate the expression profiles of EGFR in three forms of IIPs, including idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), and nonspecific interstitial pneumonia (NSIP). Patients and Methods. Twenty newly diagnosed patients with IPF, 15 with COP, and 15 with NSIP (cellular, and fibrotic, ) were investigated. Fifteen paraffin blocks obtained from the normal part of lungs removed for benign lesions were used as controls. Immunohistochemistry was carried out using specific monoclonal antibody. Results were verified by qRT-PCR. Results. A significant EGFR upregulation, both in protein and mRNA level, was observed in IPF, COP, and fibrotic NSIP samples compared to controls. EGFR was primarily localized in the hyperplastic alveolar epithelium surrounding areas of fibrosis in IPF, COP, and fibrotic NSIP samples, as assessed by double immunohistochemistry analysis with surfactant protein-A. EGFR mRNA levels were positively associated with indicators of lung fibrosis (type 1 collagen mRNA levels) and negatively correlated with functional prognostic parameters. Conclusions. We conclude that EGFR is upregulated in the hyperplastic alveolar epithelium in all three fibrotic forms of IIPs indicating a potential role during abnormal reepithelization. Argyris Tzouvelekis, Paschalis Ntolios, Andreas Karameris, George Vilaras, Panagiotis Boglou, Andreas Koulelidis, Kostas Archontogeorgis, Konstantinos Kaltsas, George Zacharis, Evangelia Sarikloglou, Paschalis Steiropoulos, Dimitrios Mikroulis, Anastasios Koutsopoulos, Marios Froudarakis, and Demosthenes Bouros Copyright © 2013 Argyris Tzouvelekis et al. All rights reserved. The Rabbit as a Model for Studying Lung Disease and Stem Cell Therapy Mon, 08 Apr 2013 17:46:36 +0000 No single animal model can reproduce all of the human features of both acute and chronic lung diseases. However, the rabbit is a reliable model and clinically relevant facsimile of human disease. The similarities between rabbits and humans in terms of airway anatomy and responses to inflammatory mediators highlight the value of this species in the investigation of lung disease pathophysiology and in the development of therapeutic agents. The inflammatory responses shown by the rabbit model, especially in the case of asthma, are comparable with those that occur in humans. The allergic rabbit model has been used extensively in drug screening tests, and this model and humans appear to be sensitive to similar drugs. In addition, recent studies have shown that the rabbit serves as a good platform for cell delivery for the purpose of stem-cell-based therapy. Nurfatin Asyikhin Kamaruzaman, Egi Kardia, Nurulain ‘Atikah Kamaldin, Ahmad Zaeri Latahir, and Badrul Hisham Yahaya Copyright © 2013 Nurfatin Asyikhin Kamaruzaman et al. All rights reserved. Sesame Oil Attenuates Ovalbumin-Induced Pulmonary Edema and Bronchial Neutrophilic Inflammation in Mice Thu, 04 Apr 2013 16:16:11 +0000 Background. Allergic asthma is one of the most common chronic inflammatory diseases of airways. Severe asthma may lead to hospitalization and death. Sesame oil is a natural product with anti-inflammatory property. However, the effect of sesame oil on allergic asthma has never been studied. Objective. We investigate the effect of sesame oil on pulmonary inflammation in allergic asthma model. Methods. Allergic airway inflammation was induced by sensitizing with two doses of 10 mg ovalbumin (OVA) and then challenged with 1% OVA nebulizer exposure (1 h/day) for 3 days. Sesame oil (0.25, 0.5, or 1 mL/kg/day) was given orally 30 min before each challenge. Samples were collected 24 h after the last challenge. Results. Data showed that sesame oil inhibited pulmonary edema and decreased interleukin (IL)-1β and IL-6 levels in bronchoalveolar lavage fluid in OVA-treated mice. Sesame oil also decreased pulmonary nitrite level, inducible nitric oxide synthase expression, and neutrophil infiltration induced by OVA. Further, sesame oil decreased serum IgE level in OVA-treated mice. Conclusion. Sesame oil may attenuate pulmonary edema and bronchial neutrophilic inflammation by inhibiting systemic IgE level in allergic asthma. Dur-Zong Hsu, Chuan-Teng Liu, Pei-Yi Chu, Ya-Hui Li, Srinivasan Periasamy, and Ming-Yie Liu Copyright © 2013 Dur-Zong Hsu et al. All rights reserved. A Potential Therapeutic Strategy for Malignant Mesothelioma with Gene Medicine Wed, 16 Jan 2013 09:20:31 +0000 Malignant mesothelioma, closely linked with occupational asbestos exposure, is relatively rare in the frequency, but the patient numbers are going to increase in the next few decades all over the world. The current treatment modalities are not effective in terms of the overall survival and the quality of life. Mesothelioma mainly develops in the thoracic cavity and infrequently metastasizes to extrapleural organs. A local treatment can thereby be beneficial to the patients, and gene therapy with an intrapleural administration of vectors is one of the potential therapeutics. Preclinical studies demonstrated the efficacy of gene medicine for mesothelioma, and clinical trials with adenovirus vectors showed the safety of an intrapleural injection and a possible involvement of antitumor immune responses. Nevertheless, low transduction efficiency remains the main hurdle that hinders further clinical applications. Moreover, rapid generation of antivector antibody also inhibits transgene expressions. In this paper, we review the current status of preclinical and clinical gene therapy for malignant mesothelioma and discuss potential clinical directions of gene medicine in terms of a combinatory use with anticancer agents and with immunotherapy. Yuji Tada, Hideaki Shimada, Kenzo Hiroshima, and Masatoshi Tagawa Copyright © 2013 Yuji Tada et al. All rights reserved. Chronic Alcohol Ingestion Changes the Landscape of the Alveolar Epithelium Sun, 30 Dec 2012 16:07:46 +0000 Similar to effects of alcohol on the heart, liver, and brain, the effects of ethanol (EtOH) on lung injury are preventable. Unlike other vital organ systems, however, the lethal effects of alcohol on the lung are underappreciated, perhaps because there are no signs of overt pulmonary disorder until a secondary insult, such as a bacterial infection or injury, occurs in the lung. This paper provides overview of the complex changes in the alveolar environment known to occur following both chronic and acute alcohol exposures. Contemporary animal and cell culture models for alcohol-induced lung dysfunction are discussed, with emphasis on the effect of alcohol on transepithelial transport processes, namely, epithelial sodium channel activity (ENaC). The cascading effect of tissue and phagocytic Nadph oxidase (Nox) may be triggered by ethanol exposure, and as such, alcohol ingestion and exposure lead to a prooxidative environment; thus impacting alveolar macrophage (AM) function and oxidative stress. A better understanding of how alcohol changes the landscape of the alveolar epithelium can lead to improvements in treating acute respiratory distress syndrome (ARDS) for which hospitalized alcoholics are at an increased risk. Charles A. Downs, David Trac, Elizabeth M. Brewer, Lou Ann Brown, and My N. Helms Copyright © 2013 Charles A. Downs et al. All rights reserved. Cigarette Smoke Extract Stimulates Rat Pulmonary Artery Smooth Muscle Cell Proliferation via PKC-PDGFB Signaling Mon, 11 Jun 2012 13:52:25 +0000 Accumulating evidence suggests a direct role for cigarette smoke in pulmonary vascular remodeling, which contributes to the development of pulmonary hypertension. However, the molecular mechanisms underlying this process remain poorly understood. Platelet-derived growth factor (PDGF) is a potential mitogen and chemoattractant implicated in several biological processes, including cell survival, proliferation, and migration. In this study, we investigated the effect of cigarette smoke extract (CSE) on cell proliferation of rat pulmonary artery smooth muscle cells (rPASMCs). We found that stimulation of rPASMCs with CSE significantly increased cell proliferation and promoted cell cycle progression from G1 phase to the S and G2 phases. CSE treatment also significantly upregulated the mRNA and protein levels of PDGFB and PDGFRβ. Our study also revealed that Rottlerin, an inhibitor of PKCδ signaling, prevented CSE-induced cell proliferation, attenuated the increase of S and G2 phase populations induced by CSE treatment, and downregulated PDGFB and PDGFRβ mRNA and protein levels in rPASMCs exposed to CSE. Collectively, our data demonstrated that CSE-induced cell proliferation of rPASMCs involved upregulation of the PKCδ-PDGFB pathway. Ai-ping Xing, Yong-cheng Du, Xiao-yun Hu, Jian-ying Xu, Huan-ping Zhang, Yi Li, and Xin Nie Copyright © 2012 Ai-ping Xing et al. All rights reserved. Triiodothyronine Represses MUC5AC Expression by Antagonizing Sp1 Binding to Its Promoter in Human Bronchial Epithelial HBE16 Cells Tue, 14 Feb 2012 12:21:42 +0000 Mucus hypersecretion is a distinguished feature of chronic inflammatory airway diseases. Interestingly, in this condition thyroid function is impaired with decreased level of triiodothyronine (T3), indicating potential link between low level of T3 and mucus hypersecretion. But the underlying mechanisms are poorly understood. In this study we aimed to elucidate the effect of T3 on MUC5AC secretion in human bronchial epithelial HBE16 cells and further investigate how T3 regulates MUC5AC gene expression at transcriptional level. By RT-PCR and ELISA we showed that T3 inhibited MUC5AC mRNA expression and protein secretion in HBE16 cells. Furthermore, luciferase assay and site-directed mutagenesis analysis demonstrated that T3 repressed MUC5AC expression at transcriptional level and the mechanism might partly lie in the specific inhibition of Sp1 binding to the promoter. Our results suggest that decreased T3 level leads to the release of repression of MUC5AC expression and thus contributes to mucus hypersecretion. Xiaolong Wang, Qi Li, Xiangdong Zhou, Victor P. Kolosov, and Juliy M. Perelman Copyright © 2012 Xiaolong Wang et al. All rights reserved. Engineering Airway Epithelium Wed, 08 Feb 2012 08:43:54 +0000 Airway epithelium is constantly presented with injurious signals, yet under healthy circumstances, the epithelium maintains its innate immune barrier and mucociliary elevator function. This suggests that airway epithelium has regenerative potential (I. R. Telford and C. F. Bridgman, 1990). In practice, however, airway regeneration is problematic because of slow turnover and dedifferentiation of epithelium thereby hindering regeneration and increasing time necessary for full maturation and function. Based on the anatomy and biology of the airway epithelium, a variety of tissue engineering tools available could be utilized to overcome the barriers currently seen in airway epithelial generation. This paper describes the structure, function, and repair mechanisms in native epithelium and highlights specific and manipulatable tissue engineering signals that could be of great use in the creation of artificial airway epithelium. John P. Soleas, Ana Paz, Paula Marcus, Alison McGuigan, and Thomas K. Waddell Copyright © 2012 John P. Soleas et al. All rights reserved. Small Interference RNA Targeting TLR4 Gene Effectively Attenuates Pulmonary Inflammation in a Rat Model Mon, 06 Feb 2012 11:42:40 +0000 Objective. The present study was to investigate the feasibility of adenovirus-mediated small interference RNA (siRNA) targeting Toll-like receptor 4 (TLR4) gene in ameliorating lipopolysaccharide- (LPS-) induced acute lung injury (ALI). Methods. In vitro, alveolar macrophages (AMs) were treated with Ad-siTLR4 and Ad-EFGP, respectively, for 12 h, 24 h, and 48 h, and then with LPS (100 ng/mL) for 2 h, and the function and expression of TLR4 were evaluated. In vivo, rats received intratracheal injection of 300 μL of normal saline (control group), 300 μL of Ad-EGFP (Ad-EGFP group), or 300 μL of Ad-siTLR4 (Ad-siTLR4 group) and then were intravenously treated with LPS (50 mg/kg) to induce ALI. Results. Ad-siTLR4 treatment significantly reduced TLR4 expression and production of proinflammatory cytokines following LPS treatment both in vitro and in vivo. Significant alleviation of tissue edema, microvascular protein leakage, and neutrophil infiltration was observed in the AdsiTLR4-treated animals. Conclusion. TLR4 plays a critical role in LPS-induced ALI, and transfection of Ad-siTLR4 can effectively downregulate TLR4 expression in vitro and in vivo, accompanied by alleviation of LPS-induced lung injury. These findings suggest that TLR4 may serve as a potential target in the treatment of ALI and RNA interfering targeting TLR4 expression represents a therapeutic strategy. Feixiang Wu, Yantao Liu, Xin Lv, Xuerong Miao, Yuming Sun, and Weifeng Yu Copyright © 2012 Feixiang Wu et al. All rights reserved. Acid-Base Disorders in Patients with Chronic Obstructive Pulmonary Disease: A Pathophysiological Review Wed, 01 Feb 2012 08:31:39 +0000 The authors describe the pathophysiological mechanisms leading to development of acidosis in patients with chronic obstructive pulmonary disease and its deleterious effects on outcome and mortality rate. Renal compensatory adjustments consequent to acidosis are also described in detail with emphasis on differences between acute and chronic respiratory acidosis. Mixed acid-base disturbances due to comorbidity and side effects of some drugs in these patients are also examined, and practical considerations for a correct diagnosis are provided. Cosimo Marcello Bruno and Maria Valenti Copyright © 2012 Cosimo Marcello Bruno and Maria Valenti. All rights reserved. Consumption of Hydrogen Water Reduces Paraquat-Induced Acute Lung Injury in Rats Mon, 24 Jan 2011 12:57:11 +0000 Exposure to paraquat leads to acute lung injury and oxidative stress is widely accepted as a contributor to paraquat-induced acute lung injury. Recent studies have reported that consumption of water with dissolved molecular hydrogen to a saturated level (hydrogen water) prevents oxidative stress-induced diseases. Here, we investigated whether consumption of saturated hydrogen saline protects rats against paraquat-induced acute lung injury. Adult male Sprague-Dawley (SD) rats were randomly divided into four groups: Control group; hydrogen water-only group (HW group); paraquat-only group (PQ group); paraquat and hydrogen water group (PQ  +  HW group). The rats in control group and HW group drank pure water or hydrogen water; the rats in PQ group and PQ  +  HW group were intraperitonealy injected with paraquat (35 mg/kg) and then provided pure water or hydrogen water. Both biochemical and histological lung alterations were measured. The results showed that hydrogen water ameliorated these alterations, demonstrating that hydrogen water alleviated paraquat-induced acute lung injury possibly by inhibition of oxidative damage. Shulin Liu, Kan Liu, Qiang Sun, Wenwu Liu, Weigang Xu, Petar Denoble, Hengyi Tao, and Xuejun Sun Copyright © 2011 Shulin Liu et al. All rights reserved. Induction by TNF- of IL-6 and IL-8 in Cystic Fibrosis Bronchial IB3-1 Epithelial Cells Encapsulated in Alginate Microbeads Wed, 08 Sep 2010 09:06:19 +0000 We have developed a microencapsulation procedure for the entrapment and manipulation of IB3-1 cystic fibrosis cells. The applied method is based on generation of monodisperse droplets by a vibrational nozzle. Different experimental parameters were analyzed, including frequency and amplitude of vibration, polymer pumping rate and distance between the nozzle and the gelling bath. We have found that the microencapsulation procedure does not alter the viability of the encapsulated IB3-1 cells. The encapsulated IB3-1 cells were characterized in term of secretomic profile, analyzing the culture medium by Bio-Plex strategy. The experiments demonstrated that most of the analyzed proteins, were secreted both by the free and encapsulated cells, even if in a different extent. In order to determine the biotechnological applications of this procedure, we determined whether encapsulated IB3-1 cells could be induced to pro-inflammatory responses, after treatment with TNF-. In this experimental set-up, encapsulated and free IB3-1 cells were treated with TNF-, thereafter the culture media from both cell populations were collected. As expected, TNF- induced a sharp increase in the secretion of interleukins, chemokines and growth factors. Of great interest was the evidence that induction of interleukin-6 and interleukin-8 occurs also by encapsulated IB3-1 cells. Monica Borgatti, Stefania Mazzitelli, Giulia Breveglieri, Roberto Gambari, and Claudio Nastruzzi Copyright © 2010 Monica Borgatti et al. All rights reserved. Discrepancy between mRNA and Protein Expression of Neutrophil Gelatinase-Associated Lipocalin in Bronchial Epithelium Induced by Sulfur Mustard Thu, 20 May 2010 07:57:49 +0000 Sulfur mustard (SM) is a potent vesicant that has been employed as a chemical weapon in various conflicts during the 20th century. More recently, mustard was used in the Iraq conflict against Iranian troops and civilians. At the present time there are more than 40.000 people suffering from pulmonary lesions special bronchiolitis obliterans (BOs) due to mustard gas. SM increases the endogenous production of reactive oxygen species (ROS). Neutrophil Gelatinase-associated Lipocalin 2 (Lcn2, NGAL) is a member of the lipocalin superfamily for which a variety of functions such as cellular protection against oxidative stress have been reported. Ten normal and Twenty SM-induced COPD patient individuals were studied. Assessment of NGAL expressions in healthy and the patients endobrinchial biopsies were performed by semiquantitative RT-PCR, real-time RT-PCR, and Immunohistochemistry analysis. While Normal control samples expressed same level of mRNA NGAL, expression level of mRNA-NGAL was upregulated about 1.4- to 9.8-folds compared to normal samples. No significant immunoreactivity was revealed in both samples. As we are aware this is the first report of induction of NGAL in patients exposed to SM. NGAL may play an important role in cellular protection against oxidative stress toxicity induced by mustard gas in airway wall of patients. Majid Ebrahimi, Mehryar Habibi Roudkenar, Abbas Ali Imani Fooladi, Raheleh Halabian, Mostafa Ghanei, Hisatake Kondo, and Mohammad Reza Nourani Copyright © 2010 Majid Ebrahimi et al. All rights reserved. Attenuation of Acute Lung Inflammation and Injury by Whole Body Cooling in a Rat Heatstroke Model Tue, 15 Dec 2009 14:59:56 +0000 Whole body cooling is the current therapy of choice for heatstroke because the therapeutic agents are not available. In this study, we assessed the effects of whole body cooling on several indices of acute lung inflammation and injury which might occur during heatstroke. Anesthetized rats were randomized into the following groups and given (a) no treatment or (b) whole body cooling immediately after onset of heatstroke. As compared with the normothermic controls, the untreated heatstroke rats had higher levels of pleural exudates volume and polymorphonuclear cell numbers, lung myloperoxidase activity and inducible nitric oxide synthase expression, histologic lung injury score, and bronchoalveolar proinflammatory cytokines and glutamate, and . In contrast, the values of mean arterial pressure, heart rate, , pH, and blood were all significantly lower during heatstroke. The acute lung inflammation and injury and electrolyte imbalance that occurred during heatstroke were significantly reduced by whole body cooling. In conclusion, we identified heat-induced acute lung inflammation and injury and electrolyte imbalance could be ameliorated by whole body cooling. Hsi-Hsing Yang, Ching-Ping Chang, Juei-Tang Cheng, and Mao-Tsun Lin Copyright © 2009 Hsi-Hsing Yang et al. All rights reserved. Pyrrolidine Dithiocarbamate Attenuates Paraquat-Induced Lung Injury in Rats Tue, 21 Jul 2009 12:18:46 +0000 Paraquat (PQ) has been demonstrated that the main target organ for the toxicity is the lung. This study aimed to investigate the potential protective effect of PDTC on the PQ-induced pulmonary damage. Fifty-four rats were divided into control, PQ-treated and PQ+PDTC-treated groups. Rats in the PQ group were administrated 40 mg/kg PQ by gastric gavage, and PDTC group with 40 mg/kg PQ followed by injection of 120 mg/kg PDTC (IP). On the days 3, 7, 14 and 21 after treatments, the activities of GSH-Px, SOD, MDA level and the content of HYP were measured. TGF-1 mRNA and protein were assayed by RT-PCR and ELISA. MDA level in plasma and BALF was increased and the activities of GSH-Px and SOD were decreased significantly in the PQ-treated groups () compared with control group. While the activities of GSH-Px and SOD in the PQ+PDTC-treated groups was markedly higher than that of PQ-treated groups (), and in contrast, MDA level was lower. TGF-1 mRNA and protein were significantly lower in the PQ+PDTC-treated groups than that of PQ-treated groups (). The histopathological changes in the PQ+PDTC-treated groups were milder than those of PQ groups. Our results suggested that PDTC treatment significantly attenuated paraquat-induced pulmonary damage. Xiuli Chang, Chunfeng Shao, Qing Wu, Qiangen Wu, Min Huang, and Zhijun Zhou Copyright © 2009 Xiuli Chang et al. All rights reserved. The Activation of Macrophage and Upregulation of CD40 Costimulatory Molecule in Lipopolysaccharide-Induced Acute Lung Injury Sun, 20 Apr 2008 00:00:00 +0000 To study the activation of macrophage and upregulation of costimulatory molecule of CD40 in lipopolysaccharide- (LPS-) induced acute lung injury (ALI) model, and to investigate the pathogenecy of ALI, mice were randomly divided into two groups. ALI model was created by injecting 0.2 mg/kg LPS in phosphate saline (PBS) in trachea. The pathologic changes of mice lungs were observed by HE staining at 24 and 48 hours after LPS treatment, then the alveolar septum damage, abnormal contraction, alveolar space hyperemia, and neutrophils or other inflammatory cells infiltration in the LPS group, but not in the control group, were observed. The expression of CD40 mRNA and CD40 protein molecules were higher in LPS group as compared to the control group by Northern blot and flow cytometry, respectively. Expression of Toll-like receptor-4 (TLR4) in activated macrophage (AMΦ) was higher in LPS group as compared to the control group by RT-PCR. The activation of NF-𝜅B binding to NF-𝜅B consensus oligos increased in LPS group by EMSA in macrophage. The concentrations of TNF-𝛼, MIP-2, and IL-1𝛽 cytokines from bronchoalveolar lavage fluid (BALF) were increased significantly in LPS group as compared to the control group by ELISA. The activation of AM and upregulation of costimulatory molecule CD40 induced all kinds of inflammatory cytokines releasing, then led to ALI. Therefore, both of them played vital role in the process of development of ALI. Liang Dong, Shujuan Wang, Ming Chen, Hongjia Li, and Wenxiang Bi Copyright © 2008 Liang Dong et al. All rights reserved.