BioMed Research International: Pulmonology The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . 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-𝛼 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-𝛼. In this experimental set-up, encapsulated and free IB3-1 cells were treated with TNF-𝛼, thereafter the culture media from both cell populations were collected. As expected, TNF-𝛼 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. 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-𝛽1 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 (𝑃<.05) 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 (𝑃<.05), and in contrast, MDA level was lower. TGF-𝛽1 mRNA and protein were significantly lower in the PQ+PDTC-treated groups than that of PQ-treated groups (𝑃<.05). 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.