Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Efficacy of Anakinra for Various Types of Crystal-Induced Arthritis in Complex Hospitalized Patients: A Case Series and Review of the Literature Thu, 26 Mar 2015 13:27:04 +0000 Background. There are few data on anakinra use after failure of conventional medications for crystal-induced peripheral arthritis and/or crowned dens syndrome among complex hospitalized patients. Methods. We retrospectively analyzed the outcome of six patients affected with subacute crystal-induced arthritis who had received anakinra in second or third line therapy, including three patients with crowned dens syndrome and three others with gouty arthritis. Patients’ comorbidities, reasons for anakinra use and associated drugs, and outcomes were recorded. Results. All patients presented with elevated inflammatory syndrome, systemic symptoms with poly/oligoarthritis. Except for absolute contraindications, all patients were previously treated with full or decreased dose of NSAID, colchicine, and/or glucocorticoids, with unsatisfactory response. All three gouty patients exhibited complete responses in all acute involvements under anakinra within 3 to 5 days, including one of them who needed the reintroduction of colchicine treatment that was previously unsuccessful. Crowned dens syndrome patients, including two with pseudogout and one with subacute hydroxyapatite deposition disease, needed 9 to 11 days to achieve complete response. Tolerance to anakinra was good. Conclusion. In case series of complex hospitalized patients, anakinra showed good activity in crowned dens syndrome and associated crystal-induced peripheral arthritis, with longer treatment duration than in gouty arthritis. A. Aouba, S. Deshayes, L. Frenzel, A. Decottignies, C. Pressiat, B. Bienvenu, F. Boue, G. Damaj, O. Hermine, and S. Georgin-Lavialle Copyright © 2015 A. Aouba et al. All rights reserved. CNTNAP3 Associated ATG16L1 Expression and Crohn’s Disease Thu, 26 Mar 2015 11:21:41 +0000 Autophagy is a common physiological process in cell homeostasis and regulation. Autophagy-related gene mutations and autophagy disorders are important in Crohn’s disease (CD). The nucleotide oligomerization domain 2–autophagy genes autophagy 16-like 1 (NOD2–ATG16L1) signaling axis disorder contributes to the dysfunction of autophagy. This paper is focused on the relationship between contactin associated protein-like 3 (CNTNAP3) and ATG16L1 expression in Crohn’s disease. The results indicated that the expression of ATG16L1 is higher in some CD patients compared to normal controls. ATG16L1 was well correlated with the C-reactive protein (CRP) in some CD patients. In vitro study revealed that CNTNAP3 could upregulate the expression of ATG16L1 and increase autophagy vacuoles. Yu Qi Qiao, Mei Lan Huang, Qing Zheng, Tian Rong Wang, An Tao Xu, Yuan Cao, Di Zhao, Zhi Hua Ran, and Jun Shen Copyright © 2015 Yu Qi Qiao et al. All rights reserved. Inflammation in Sleep Debt and Sleep Disorders Wed, 25 Mar 2015 12:33:09 +0000 Leila Kheirandish-Gozal, David Gozal, and Jean-Louis Pépin Copyright © 2015 Leila Kheirandish-Gozal et al. All rights reserved. Impaired Fracture Healing after Hemorrhagic Shock Wed, 25 Mar 2015 11:15:04 +0000 Impaired fracture healing can occur in severely injured patients with hemorrhagic shock due to decreased soft tissue perfusion after trauma. We investigated the effects of fracture healing in a standardized pressure controlled hemorrhagic shock model in mice, to test the hypothesis that bleeding is relevant in the bone healing response. Male C57/BL6 mice were subjected to a closed femoral shaft fracture stabilized by intramedullary nailing. One group was additionally subjected to pressure controlled hemorrhagic shock (HS, mean arterial pressure (MAP) of 35 mmHg for 90 minutes). Serum cytokines (IL-6, KC, MCP-1, and TNF-) were analyzed 6 hours after shock. Fracture healing was assessed 21 days after fracture. Hemorrhagic shock is associated with a significant increase in serum inflammatory cytokines in the early phase. Histologic analysis demonstrated a significantly decreased number of osteoclasts, a decrease in bone quality, and more cartilage islands after hemorrhagic shock. μCT analysis showed a trend towards decreased bone tissue mineral density in the HS group. Mechanical testing revealed no difference in tensile failure. Our results suggest a delay in fracture healing after hemorrhagic shock. This may be due to significantly diminished osteoclast recruitment. The exact mechanisms should be studied further, particularly during earlier stages of fracture healing. Philipp Lichte, Philipp Kobbe, Roman Pfeifer, Graeme C. Campbell, Rainer Beckmann, Mersedeh Tohidnezhad, Christian Bergmann, Mamed Kadyrow, Horst Fischer, Christian C. Glüer, Frank Hildebrand, Hans-Christoph Pape, and Thomas Pufe Copyright © 2015 Philipp Lichte et al. All rights reserved. The Inflammatory Actions of Coagulant and Fibrinolytic Proteases in Disease Tue, 24 Mar 2015 13:28:51 +0000 Aside from their role in hemostasis, coagulant and fibrinolytic proteases are important mediators of inflammation in diseases such as asthma, atherosclerosis, rheumatoid arthritis, and cancer. The blood circulating zymogens of these proteases enter damaged tissue as a consequence of vascular leak or rupture to become activated and contribute to extravascular coagulation or fibrinolysis. The coagulants, factor Xa (FXa), factor VIIa (FVIIa), tissue factor, and thrombin, also evoke cell-mediated actions on structural cells (e.g., fibroblasts and smooth muscle cells) or inflammatory cells (e.g., macrophages) via the proteolytic activation of protease-activated receptors (PARs). Plasmin, the principle enzymatic mediator of fibrinolysis, also forms toll-like receptor-4 (TLR-4) activating fibrin degradation products (FDPs) and can release latent-matrix bound growth factors such as transforming growth factor-β (TGF-β). Furthermore, the proteases that convert plasminogen into plasmin (e.g., urokinase plasminogen activator) evoke plasmin-independent proinflammatory actions involving coreceptor activation. Selectively targeting the receptor-mediated actions of hemostatic proteases is a strategy that may be used to treat inflammatory disease without the bleeding complications of conventional anticoagulant therapies. The mechanisms by which proteases of the coagulant and fibrinolytic systems contribute to extravascular inflammation in disease will be considered in this review. Michael Schuliga Copyright © 2015 Michael Schuliga. All rights reserved. Role of Polymorphisms of Inducible Nitric Oxide Synthase and Endothelial Nitric Oxide Synthase in Idiopathic Environmental Intolerances Tue, 24 Mar 2015 12:54:58 +0000 Oxidative stress and inflammation play a pathogenetic role in idiopathic environmental intolerances (IEI), namely, multiple chemical sensitivity (MCS), fibromyalgia (FM), and chronic fatigue syndrome (CFS). Given the reported association of nitric oxide synthase (NOS) gene polymorphisms with inflammatory disorders, we aimed to investigate the distribution of NOS2A −2.5 kb (CCTTT)n as well as Ser608Leu and NOS3 −786T>C variants and their correlation with nitrite/nitrate levels, in a study cohort including 170 MCS, 108 suspected MCS (SMCS), 89 FM/CFS, and 196 healthy subjects. Patients and controls had similar distributions of NOS2A Ser608Leu and NOS3 −786T>C polymorphisms. Interestingly, the NOS3 −786TT genotype was associated with increased nitrite/nitrate levels only in IEI patients. We also found that the NOS2A −2.5 kb (CCTTT)11 allele represents a genetic determinant for FM/CFS, and the (CCTTT)16 allele discriminates MCS from SMCS patients. Instead, the (CCTTT)8 allele reduces by three-, six-, and tenfold, respectively, the risk for MCS, SMCS, and FM/CFS. Moreover, a short number of (CCTTT) repeats is associated with higher concentrations of nitrites/nitrates. Here, we first demonstrate that NOS3 −786T>C variant affects nitrite/nitrate levels in IEI patients and that screening for NOS2A −2.5 kb (CCTTT)n polymorphism may be useful for differential diagnosis of various IEI. Chiara De Luca, Agnese Gugliandolo, Carlo Calabrò, Monica Currò, Riccardo Ientile, Desanka Raskovic, Ludmila Korkina, and Daniela Caccamo Copyright © 2015 Chiara De Luca et al. All rights reserved. Inflammation in the Disease: Mechanism and Therapies 2014 Tue, 24 Mar 2015 09:33:51 +0000 M. Seelaender, J. C. Rosa Neto, G. D. Pimentel, R. S. Goldszmid, and F. S. Lira Copyright © 2015 M. Seelaender et al. All rights reserved. The Utility of Iron Chelators in the Management of Inflammatory Disorders Mon, 23 Mar 2015 12:43:46 +0000 Since iron can contribute to detrimental radical generating processes through the Fenton and Haber-Weiss reactions, it seems to be a reasonable approach to modulate iron-related pathways in inflammation. In the human organism a counterregulatory reduction in iron availability is observed during inflammatory diseases. Under pathological conditions with reduced or increased baseline iron levels different consequences regarding protection or susceptibility to inflammation have to be considered. Given the role of iron in development of inflammatory diseases, pharmaceutical agents targeting this pathway promise to improve the clinical outcome. The objective of this review is to highlight the mechanisms of iron regulation and iron chelation, and to demonstrate the potential impact of this strategy in the management of several acute and chronic inflammatory diseases, including cancer. C. Lehmann, S. Islam, S. Jarosch, J. Zhou, D. Hoskin, A. Greenshields, N. Al-Banna, N. Sharawy, A. Sczcesniak, M. Kelly, K. Wafa, W. Cheliak, and B. Holbein Copyright © 2015 C. Lehmann et al. All rights reserved. Oxygen-Loaded Nanodroplets Effectively Abrogate Hypoxia Dysregulating Effects on Secretion of MMP-9 and TIMP-1 by Human Monocytes Mon, 23 Mar 2015 12:36:13 +0000 Monocytes play a key role in the inflammatory stage of the healing process. To allow monocyte migration to injured tissues, the balances between secreted matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) must be finely modulated. However, a reduction of blood supply and local oxygen tension can modify the phenotype of immune cells. Intriguingly, hypoxia might be targeted by new effective oxygenating devices such as 2H,3H-decafluoropentane- (DFP-) based oxygen-loaded nanodroplets (OLNs). Here, hypoxia effects on gelatinase/TIMP release from human peripheral monocytes were investigated, and the therapeutic potential of dextran-shelled OLNs was evaluated. Normoxic monocytes constitutively released ~500 ng/mL MMP-9, ~1.3 ng/mL TIMP-1, and ~0.6 ng/mL TIMP-2 proteins. MMP-2 was not detected. After 24 hours, hypoxia significantly altered MMP-9/TIMP-1 balance by reducing MMP-9 and increasing TIMP-1, without affecting TIMP-2 secretion. Interestingly OLNs, not displaying toxicity to human monocytes after cell internalization, effectively counteracted hypoxia, restoring a normoxia-like MMP-9/TIMP-1 ratio. The action of OLNs was specifically dependent on time-sustained oxygen diffusion up to 24 h from their DFP-based core. Therefore, OLNs appear as innovative, nonconventional, cost-effective, and nontoxic therapeutic tools, to be potentially employed to restore the physiological invasive phenotype of immune cells in hypoxia-associated inflammation. Giulia Rossana Gulino, Chiara Magnetto, Amina Khadjavi, Alice Panariti, Ilaria Rivolta, Marco Soster, Monica Argenziano, Roberta Cavalli, Giuliana Giribaldi, Caterina Guiot, and Mauro Prato Copyright © 2015 Giulia Rossana Gulino et al. All rights reserved. Cellular Mechanisms Underlying Eosinophilic and Neutrophilic Airway Inflammation in Asthma Mon, 23 Mar 2015 09:40:05 +0000 Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments. Girolamo Pelaia, Alessandro Vatrella, Maria Teresa Busceti, Luca Gallelli, Cecilia Calabrese, Rosa Terracciano, and Rosario Maselli Copyright © 2015 Girolamo Pelaia et al. All rights reserved. Hydrogen-Rich Saline Attenuates Acute Renal Injury in Sodium Taurocholate-Induced Severe Acute Pancreatitis by Inhibiting ROS and NF-κB Pathway Mon, 23 Mar 2015 09:39:07 +0000 Hydrogen (H2), a new antioxidant, was reported to reduce •OH and ONOO− selectively and inhibit certain proinflammatory mediators to product, without disturbing metabolic redox reactions or ROS involved in cell signaling. We herein aim to explore its protective effects on acute renal injury in sodium taurocholate-induced acute pancreatitis and its possible mechanisms. Rats were injected with hydrogen-rich saline (HRS group) or normal saline (SO and SAP group) through tail intravenously (6 mL/kg) and compensated subcutaneously (20 mL/kg) after successful modeling. Results showed that hydrogen-rich saline attenuated the following: (1) serum Cr and BUN, (2) pancreatic and renal pathological injuries, (3) renal MDA, (4) renal MPO, (5) serum IL-1β, IL-6, and renal TNF-α, HMGB1, and (6) tyrosine nitration, IκB degradation, and NF-κB activation in renal tissues. In addition, it increased the level of IL-10 and SOD activity in renal tissues. These results proved that hydrogen-rich saline attenuates acute renal injury in sodium taurocholate-induced acute pancreatitis, presumably because of its detoxification activity against excessive ROS, and inhibits the activation of NF-κB by affecting IκB nitration and degradation. Our findings highlight the potential value of hydrogen-rich saline as a new therapeutic method on acute renal injury in severe acute pancreatitis clinically. Qiao Shi, Kang-Shu Liao, Kai-Liang Zhao, Wei-Xing Wang, Teng Zuo, Wen-Hong Deng, Chen Chen, Jia Yu, Wen-Yi Guo, Xiao-Bo He, Ablikim Abliz, Peng Wang, and Liang Zhao Copyright © 2015 Qiao Shi et al. All rights reserved. Effects of the Mitochondria-Targeted Antioxidant Mitoquinone in Murine Acute Pancreatitis Mon, 23 Mar 2015 07:24:09 +0000 Although oxidative stress has been strongly implicated in the development of acute pancreatitis (AP), antioxidant therapy in patients has so far been discouraging. The aim of this study was to assess potential protective effects of a mitochondria-targeted antioxidant, MitoQ, in experimental AP using in vitro and in vivo approaches. MitoQ blocked H2O2-induced intracellular ROS responses in murine pancreatic acinar cells, an action not shared by the control analogue dTPP. MitoQ did not reduce mitochondrial depolarisation induced by either cholecystokinin (CCK) or bile acid TLCS, and at 10 µM caused depolarisation per se. Both MitoQ and dTPP increased basal and CCK-induced cell death in a plate-reader assay. In a TLCS-induced AP model MitoQ treatment was not protective. In AP induced by caerulein hyperstimulation (CER-AP), MitoQ exerted mixed effects. Thus, partial amelioration of histopathology scores was observed, actions shared by dTPP, but without reduction of the biochemical markers pancreatic trypsin or serum amylase. Interestingly, lung myeloperoxidase and interleukin-6 were concurrently increased by MitoQ in CER-AP. MitoQ caused biphasic effects on ROS production in isolated polymorphonuclear leukocytes, inhibiting an acute increase but elevating later levels. Our results suggest that MitoQ would be inappropriate for AP therapy, consistent with prior antioxidant evaluations in this disease. Wei Huang, Nicole Cash, Li Wen, Peter Szatmary, Rajarshi Mukherjee, Jane Armstrong, Michael Chvanov, Alexei V. Tepikin, Michael P. Murphy, Robert Sutton, and David N. Criddle Copyright © 2015 Wei Huang et al. All rights reserved. Effect of Helicobacter pylori Eradication on TLR2 and TLR4 Expression in Patients with Gastric Lesions Sun, 22 Mar 2015 12:50:45 +0000 Objective. Helicobacter pylori (Hp) is recognized by TLR4 and TLR2 receptors, which trigger the activation of genes involved in the host immune response. Thus, we evaluated the effect of eradication therapy on TLR2 and TLR4 mRNA and protein expression in H. pylori-infected chronic gastritis patients (CG-Hp+) and 3 months after treatment. Methods. A total of 37 patients CG-Hp+ were evaluated. The relative quantification (RQ) of mRNA was assessed by TaqMan assay and protein expression by immunohistochemistry. Results. Before treatment both TLR2 and TLR4 mRNA in CG-Hp+ patients were slightly increased (TLR2 = 1.32; TLR4 = 1.26) in relation to Hp-negative normal gastric mucosa (). After successful eradication therapy no significant change was observed (TLR2 = 1.47; TLR4 = 1.53; ). In addition, the cagA and vacA bacterial genotypes did not influence the gene expression levels, and we observed a positive correlation between the RQ values of TLR2 and TLR4, both before and after treatment. Immunoexpression of the TLR2 and TLR4 proteins confirmed the gene expression results. Conclusion. In conclusion, the expression of both TLR2 and TLR4 is increased in CG-Hp+ patients regardless of cagA and vacA status and this expression pattern is not significantly changed after eradication of bacteria, at least for the short period of time evaluated. Aline Cristina Targa Cadamuro, Ana Flávia Teixeira Rossi, Joice Matos Biselli-Périco, Patrícia Fucuta Pereira, Edla Polsinelli Bedin Mascarin Do Vale, Ricardo Acayaba, Kátia Ramos Moreira Leite, Eny Maria Goloni-Bertollo, and Ana Elizabete Silva Copyright © 2015 Aline Cristina Targa Cadamuro et al. All rights reserved. Fas/FasL Pathway Participates in Regulation of Antiviral and Inflammatory Response during Mousepox Infection of Lungs Sun, 22 Mar 2015 12:38:37 +0000 Fas receptor-Fas ligand (FasL) signalling is involved in apoptosis of immune cells as well as of the virus infected target cells but increasing evidence accumulates on Fas as a mediator of apoptosis-independent processes such as induction of activating and proinflammatory signals. In this study, we examined the role of Fas/FasL pathway in inflammatory and antiviral response in lungs using a mousepox model applied to C57BL6/J, B6. MRL-Faslpr/J, and B6Smn.C3-Faslgld/J mice. Ectromelia virus (ECTV) infection of Fas- and FasL-deficient mice led to increased virus titers in lungs and decreased migration of IFN-γ expressing NK cells, CD4+ T cells, CD8+ T cells, and decreased IL-15 expression. The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression. Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis. Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response. Karolina Bień, Justyna Sokołowska, Piotr Bąska, Zuzanna Nowak, Wanda Stankiewicz, and Malgorzata Krzyzowska Copyright © 2015 Karolina Bień et al. All rights reserved. 5′-Adenosine Monophosphate-Induced Hypothermia Attenuates Brain Ischemia/Reperfusion Injury in a Rat Model by Inhibiting the Inflammatory Response Sun, 22 Mar 2015 12:37:59 +0000 Hypothermia treatment is a promising therapeutic strategy for brain injury. We previously demonstrated that 5′-adenosine monophosphate (5′-AMP), a ribonucleic acid nucleotide, produces reversible deep hypothermia in rats when the ambient temperature is appropriately controlled. Thus, we hypothesized that 5′-AMP-induced hypothermia (AIH) may attenuate brain ischemia/reperfusion injury. Transient cerebral ischemia was induced by using the middle cerebral artery occlusion (MCAO) model in rats. Rats that underwent AIH treatment exhibited a significant reduction in neutrophil elastase infiltration into neuronal cells and matrix metalloproteinase 9 (MMP-9), interleukin-1 receptor (IL-1R), tumor necrosis factor receptor (TNFR), and Toll-like receptor (TLR) protein expression in the infarcted area compared to euthermic controls. AIH treatment also decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL-) positive neuronal cells. The overall infarct volume was significantly smaller in AIH-treated rats, and neurological function was improved. By contrast, rats with ischemic brain injury that were administered 5′-AMP without inducing hypothermia had ischemia/reperfusion injuries similar to those in euthermic controls. Thus, the neuroprotective effects of AIH were primarily related to hypothermia. Yi-Feng Miao, Hui Wu, Shao-Feng Yang, Jiong Dai, Yong-Ming Qiu, Zhen-Yi Tao, and Xiao-Hua Zhang Copyright © 2015 Yi-Feng Miao et al. All rights reserved. Contribution of Microglia-Mediated Neuroinflammation to Retinal Degenerative Diseases Sun, 22 Mar 2015 11:34:33 +0000 Retinal degenerative diseases are major causes of vision loss and blindness worldwide and are characterized by chronic and progressive neuronal loss. One common feature of retinal degenerative diseases and brain neurodegenerative diseases is chronic neuroinflammation. There is growing evidence that retinal microglia, as in the brain, become activated in the course of retinal degenerative diseases, having a pivotal role in the initiation and propagation of the neurodegenerative process. A better understanding of the events elicited and mediated by retinal microglia will contribute to the clarification of disease etiology and might open new avenues for potential therapeutic interventions. This review aims at giving an overview of the roles of microglia-mediated neuroinflammation in major retinal degenerative diseases like glaucoma, age-related macular degeneration, and diabetic retinopathy. Maria H. Madeira, Raquel Boia, Paulo F. Santos, António F. Ambrósio, and Ana R. Santiago Copyright © 2015 Maria H. Madeira et al. All rights reserved. The Role of the Immune System in Triplet Repeat Expansion Diseases Sun, 22 Mar 2015 11:02:13 +0000 Trinucleotide repeat expansion disorders (TREDs) are a group of dominantly inherited neurological diseases caused by the expansion of unstable repeats in specific regions of the associated genes. Expansion of CAG repeat tracts in translated regions of the respective genes results in polyglutamine- (polyQ-) rich proteins that form intracellular aggregates that affect numerous cellular activities. Recent evidence suggests the involvement of an RNA toxicity component in polyQ expansion disorders, thus increasing the complexity of the pathogenic processes. Neurodegeneration, accompanied by reactive gliosis and astrocytosis is the common feature of most TREDs, which may suggest involvement of inflammation in pathogenesis. Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease. Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression. Herein, we review the involvement of the immune system in the pathogenesis of triplet repeat expansion diseases, with particular emphasis on polyglutamine disorders. We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases. Marta Olejniczak, Martyna O. Urbanek, and Wlodzimierz J. Krzyzosiak Copyright © 2015 Marta Olejniczak et al. All rights reserved. Blockade of the JNK Signalling as a Rational Therapeutic Approach to Modulate the Early and Late Steps of the Inflammatory Cascade in Polymicrobial Sepsis Sun, 22 Mar 2015 10:08:49 +0000 Cecal ligation and puncture (CLP) is an experimental polymicrobial sepsis induced systemic inflammation that leads to acute organ failure. Aim of our study was to evaluate the effects of SP600125, a specific c-Jun NH2-terminal kinase (JNK) inhibitor, to modulate the early and late steps of the inflammatory cascade in a murine model of CLP-induced sepsis. CB57BL/6J mice were subjected to CLP or sham operation. Animals were randomized to receive either SP600125 (15 mg/kg) or its vehicle intraperitoneally 1 hour after surgery and repeat treatment every 24 hours. To evaluate survival, a group of animals was monitored every 24 hours for 120 hours. Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis. The expression of p-JNK, p-ERK, TNF-α, HMGB-1, NF-κB, Ras, Rho, Caspase 3, Bcl-2, and Bax was evaluated in lung and liver samples; SP600125 improved survival, reduced CLP induced activation of JNK, NF-κB, TNF-α, and HMGB-1, inhibited proapoptotic pathway, preserved Bcl-2 expression, and reduced histologic damage in both lung and liver of septic mice. SP600125 protects against CLP induced sepsis by blocking JNK signalling; therefore, it can be considered a therapeutic approach in human sepsis. Gabriele Pizzino, Alessandra Bitto, Giovanni Pallio, Natasha Irrera, Federica Galfo, Monica Interdonato, Anna Mecchio, Filippo De Luca, Letteria Minutoli, Francesco Squadrito, and Domenica Altavilla Copyright © 2015 Gabriele Pizzino et al. All rights reserved. Improved Fracture Healing in Patients with Concomitant Traumatic Brain Injury: Proven or Not? Sun, 22 Mar 2015 09:59:50 +0000 Over the last 3 decades, scientific evidence advocates an association between traumatic brain injury (TBI) and accelerated fracture healing. Multiple clinical and preclinical studies have shown an enhanced callus formation and an increased callus volume in patients, respectively, rats with concomitant TBI. Over time, different substances (cytokines, hormones, etc.) were in focus to elucidate the relationship between TBI and fracture healing. Until now, the mechanism behind this relationship is not fully clarified and a consensus on which substance plays the key role could not be attained in the literature. In this review, we will give an overview of current concepts and opinions on this topic published in the last decade and both clinical and pathophysiological theories will be discussed. Martijn Hofman, Guido Koopmans, Philipp Kobbe, Martijn Poeze, Hagen Andruszkow, Peter R. G. Brink, and Hans-Christoph Pape Copyright © 2015 Martijn Hofman et al. All rights reserved. Relationship between Gingival Inflammation and Pregnancy Sun, 22 Mar 2015 09:28:49 +0000 An increase in the prevalence and severity of gingival inflammation during pregnancy has been reported since the 1960s. Though the etiology is not fully known, it is believed that increasing plasma sex steroid hormone levels during pregnancy have a dramatic effect on the periodontium. Current works of research have shown that estrogen and progesterone increasing during pregnancy are supposed to be responsible for gingivitis progression. This review is focused not only on epidemiological studies, but also on the effects of progesterone and estrogen on the change of subgingival microbiota and immunologic physiological mediators in periodontal tissue (gingiva and periodontal ligament), which provides current information about the effects of pregnancy on gingival inflammation. Min Wu, Shao-Wu Chen, and Shao-Yun Jiang Copyright © 2015 Min Wu et al. All rights reserved. Hydrogen-Rich Saline Protects against Ischemia/Reperfusion Injury in Grafts after Pancreas Transplantations by Reducing Oxidative Stress in Rats Sun, 22 Mar 2015 09:18:43 +0000 Purpose. This study aimed to investigate the therapeutic potential of hydrogen-rich saline on pancreatic ischemia/reperfusion (I/R) injury in rats. Methods. Eighty heterotopic pancreas transplantations (HPT) were performed in syngenic rats. The receptors were randomized blindly into the following three groups: the HPT group and two groups that underwent transplantation and administration of hydrogen-rich saline (HS, >0.6 mM, 6 mL/kg) or normal saline (NS, 6 mL/kg) via the tail vein at the beginning of reperfusion (HPT + HS group, HPT + NS group). Samples from the pancreas and blood were taken at 12 hours after reperfusion. The protective effects of hydrogen-rich saline against I/R injury were evaluated by determining the changes in histopathology and measuring serological parameters, oxidative stress-associated molecules, and proinflammatory cytokines. Results. Administration of hydrogen-rich saline produced notable protection against pancreatic I/R injury in rats. Histopathological improvements and recovery of impaired pancreatic function were observed. In addition, TNF-α, IL-1β, and IL-6 were reduced markedly in the HPT + HS group. Additionally, there were noticeable inhibitory effects on the pancreatic malondialdehyde level and considerable recruitment of SOD and GPx, which are antioxidants. Conclusion. Hydrogen-rich saline treatment significantly attenuated the severity of pancreatic I/R injury in rats, possibly by reducing oxidative stress and inflammation. Zhu-Lin Luo, Long Cheng, Jian-Dong Ren, Chen Fang, Ke Xiang, Hao-Tong Xu, Li-Jun Tang, Tao Wang, and Fu-Zhou Tian Copyright © 2015 Zhu-Lin Luo et al. All rights reserved. Pantoprazole Decreases Cell Viability and Function of Human Osteoclasts In Vitro Sun, 22 Mar 2015 09:07:56 +0000 Proton pump inhibitors (PPIs) are commonly prescribed drugs that decrease stomach acidity and are thus often used to treat gastroesophageal reflux disease and as a preventative agent for the adverse effects of nonsteroidal anti-inflammatory drugs on the stomach mucosa. In recently published literature, an association between proton pump inhibitor administration and increased fracture risk has been stated. In order to reveal the underlying pathomechanisms of these observations, the effects of pantoprazole, a representative of the proton pump inhibitors, on human osteoclasts in vitro were evaluated in this study. Osteoclasts were stimulated with increasing concentrations of pantoprazole ranging from 0 μg/mL to 10 μg/mL over a period of seven days. Cell viability and tartrate-resistant acid phosphatase (TRAP) activity assays were performed after 1 day, 3 days, and 7 days, respectively. Here, stimulated osteoclasts presented a significantly lower viability and TRAP activity than the negative controls. Osteoclast-specific gene expression was evaluated after seven days and revealed no significant differences between all samples. Overall, the bone degrading and resorptive function of osteoclasts is inhibited by the administration of proton pump inhibitors. While PPI-related fractures through “basic multicellular unit” dysfunction are unlikely, the underlying pathomechanism remains unknown. Markus Prause, Claudine Seeliger, Marina Unger, Elizabeth Rosado Balmayor, Martijn van Griensven, and Alexander Tobias Haug Copyright © 2015 Markus Prause et al. All rights reserved. Acute Necrotizing Encephalopathy: An Underrecognized Clinicoradiologic Disorder Sun, 22 Mar 2015 09:02:12 +0000 Acute necrotizing encephalopathy (ANE) is a rare but distinctive type of acute encephalopathy with global distribution. Occurrence of ANE is usually preceded by a virus-associated febrile illness and ensued by rapid deterioration. However, the causal relationship between viral infections and ANE and the exact pathogenesis of ANE remain unclear; both environmental and host factors might be involved. Most cases of ANE are sporadic and nonrecurrent, namely, isolated or sporadic ANE; however, few cases are recurrent and with familial episodes. The recurrent and familial forms of ANE were found to be incompletely autosomal-dominant. Further the missense mutations in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2) were identified. Although the clinical course and the prognosis of ANE are diverse, the hallmark of neuroradiologic manifestation of ANE is multifocal symmetric brain lesions which are demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI). The treatment of ANE is still under investigation. We summarize the up-to-date knowledge on ANE, with emphasis on prompt diagnosis and better treatment of this rare but fatal disease. Xiujuan Wu, Wei Wu, Wei Pan, Limin Wu, Kangding Liu, and Hong-Liang Zhang Copyright © 2015 Xiujuan Wu et al. All rights reserved. Excessive Daytime Sleepiness Is Associated with Changes in Salivary Inflammatory Genes Transcripts Sun, 22 Mar 2015 08:55:43 +0000 Excessive daytime sleepiness (EDS) is a ubiquitous problem that affects public health and safety. A test that can reliably identify individuals that suffer from EDS is needed. In contrast to other methods, salivary biomarkers are an objective, inexpensive, and noninvasive method to identify individuals with inadequate sleep. Although we have previously shown that inflammatory genes are elevated in saliva samples taken from sleep deprived individuals, it is unclear if inflammatory genes will be elevated in clinical populations with EDS. In this study, salivary samples from individuals with sleep apnea were evaluated using the Taqman low density inflammation array. Transcript levels for 3 genes, including prostaglandin-endoperoxide synthase 2 (PTGS2), were elevated in patients with sleep apnea. Interestingly, PTGS2 was also elevated in patients with EDS but who did not have sleep apnea. These data demonstrate the feasibility of using salivary transcript levels to identify individuals that self-report excessive daytime sleepiness. Matthew S. Thimgan, Cristina Toedebusch, Jennifer McLeland, Stephen P. Duntley, and Paul J. Shaw Copyright © 2015 Matthew S. Thimgan et al. All rights reserved. Thiopurines Induce Oxidative Stress in T-Lymphocytes: A Proteomic Approach Sun, 22 Mar 2015 08:52:29 +0000 Thiopurines are extensively used immunosuppressants for the treatment of inflammatory bowel disease (IBD). The polymorphism of thiopurine S-methyltransferase (TPMT) influences thiopurine metabolism and therapy outcome. We used a TPMT knockdown (kd) model of human Jurkat T-lymphocytes cells to study the effects of treatment with 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) on proteome and phosphoproteome. We identified thirteen proteins with altered expression and nine proteins with altered phosphorylation signals. Three proteins (THIO, TXD17, and GSTM3) with putative functions in cellular oxidative stress responses were altered by 6-TG treatment and another protein PRDX3 was differentially phosphorylated in TPMT kd cells. Furthermore, reactive oxygen species (ROS) assay results were consistent with a significant induction of oxidative stress by both TPMT knockdown and thiopurine treatments. Immunoblot analyses showed treatment altered expression of key antioxidant enzymes (i.e., SOD2 and catalase) in both wt and kd groups, while SOD1 was downregulated by 6-TG treatment and TPMT knockdown. Collectively, increased oxidative stress might be a mechanism involved in thiopurine induced cytotoxicity and adverse effects (i.e., hepatotoxicity) and an antioxidant cotherapy might help to combat this. Results highlight the significance of oxidative stress in thiopurines’ actions and could have important implications for the treatment of IBD patients. Misbah Misdaq, Sonia Ziegler, Nicolas von Ahsen, Michael Oellerich, and Abdul R. Asif Copyright © 2015 Misbah Misdaq et al. All rights reserved. Interleukin-18 Increases TLR4 and Mannose Receptor Expression and Modulates Cytokine Production in Human Monocytes Thu, 19 Mar 2015 13:10:32 +0000 Interleukin-18 is a proinflammatory cytokine belonging to the interleukin-1 family of cytokines. This cytokine exerts many unique biological and immunological effects. To explore the role of IL-18 in inflammatory innate immune responses, we investigated its impact on expression of two toll-like receptors (TLR2 and TLR4) and mannose receptor (MR) by human peripheral blood monocytes and its effect on TNF-α, IL-12, IL-15, and IL-10 production. Monocytes from healthy donors were stimulated or not with IL-18 for 18 h, and then the TLR2, TLR4, and MR expression and intracellular TNF-α, IL-12, and IL-10 production were assessed by flow cytometry and the levels of TNF-α, IL-12, IL-15, and IL-10 in culture supernatants were measured by ELISA. IL-18 treatment was able to increase TLR4 and MR expression by monocytes. The production of TNF-α and IL-10 was also increased by cytokine treatment. However, IL-18 was unable to induce neither IL-12 nor IL-15 production by these cells. Taken together, these results show an important role of IL-18 on the early phase of inflammatory response by promoting the expression of some pattern recognition receptors (PRRs) that are important during the microbe recognition phase and by inducing some important cytokines such as TNF-α and IL-10. Luciane Alarcão Dias-Melicio, Reginaldo Keller Fernandes, Daniela Ramos Rodrigues, Marjorie Assis Golim, and Angela Maria Victoriano Campos Soares Copyright © 2015 Luciane Alarcão Dias-Melicio et al. All rights reserved. Toll-Like Receptor-4 Mediated Inflammation Is Involved in the Cardiometabolic Alterations Induced by Intermittent Hypoxia Thu, 19 Mar 2015 12:19:24 +0000 Objective. Intermittent hypoxia (IH) is a major component of sleep apnea syndrome as its cardiometabolic complications have been mainly attributed to IH. The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications. As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH. Methods. Lean adult male TLR4-deficient (TLR4−/−) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 21-5%, 1 min cycle, 8 h/day) or air (normoxic mice) for 4 weeks. Animals were assessed at 1-week exposure for insulin tolerance test and after 4-week exposure for morphological and inflammatory changes of the epididymal fat and thoracic aorta. Results. IH induced insulin resistance, morphological and inflammatory changes of the epididymal fat (smaller pads and adipocytes, higher release of TNF-α and IL-6) and aorta (larger intima-media thickness and higher NFκB-p50 activity). All these alterations were prevented by TLR4 deletion. Conclusion. IH induces metabolic and vascular alterations that involve TLR4 mediated inflammation. These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients. Laureline Poulain, Vincent Richard, Patrick Lévy, Maurice Dematteis, and Claire Arnaud Copyright © 2015 Laureline Poulain et al. All rights reserved. OSAS-Related Inflammatory Mechanisms of Liver Injury in Nonalcoholic Fatty Liver Disease Thu, 19 Mar 2015 11:45:27 +0000 Obstructive sleep apnoea syndrome (OSAS) is a common sleep disorder, affecting over 4% of the general population, and is associated with metabolic syndrome and cardiovascular disease, independent of obesity and traditional risk factors. OSAS has been recently connected to nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the world, which can be found in 30% of the general adult population. Several studies suggest that the chronic intermittent hypoxia (CIH) of OSAS patients may per se trigger liver injury, inflammation, and fibrogenesis, promoting NAFLD development and the progression from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In NAFLD patients, liver disease may be caused by hypoxia both indirectly by promoting inflammation and insulin resistance and directly by enhancing proinflammatory cytokine production and metabolic dysregulation in liver cells. In this review, we focus on molecular mechanisms linking OSAS to NAFLD, including hypoxia inducible factor (HIF), nuclear factor kappa B (NF-κB), YKL-40, unfolded protein response, and hypoxic adipose tissue inflammation, which all could provide novel potential therapeutic approaches for the management of NAFLD patients with OSAS. Elena Paschetta, Paola Belci, Anna Alisi, Daniela Liccardo, Renato Cutrera, Giovanni Musso, and Valerio Nobili Copyright © 2015 Elena Paschetta et al. All rights reserved. Immunology and Infection by Protozoan Parasites Thu, 19 Mar 2015 11:30:38 +0000 Edecio Cunha-Neto, Christophe Chevillard, Mauricio Martins Rodrigues, and Marcelo T. Bozza Copyright © 2015 Edecio Cunha-Neto et al. All rights reserved. Role of IL-38 and Its Related Cytokines in Inflammation Thu, 19 Mar 2015 11:08:25 +0000 Interleukin- (IL-) 38 is a recently discovered cytokine and is the tenth member of the IL-1 cytokine family. IL-38 shares structural features with IL-1 receptor antagonist (IL-1Ra) and IL-36Ra. IL-36R is the specific receptor of IL-38, a partial receptor antagonist of IL-36. IL-38 inhibits the production of T-cell cytokines IL-17 and IL-22. IL-38 also inhibits the production of IL-8 induced by IL-36γ, thus inhibiting inflammatory responses. IL-38-related cytokines, including IL-1Ra and IL-36Ra, are involved in the regulation of inflammation and immune responses. The study of IL-38 and IL-38-related cytokines might provide new insights for developing anti-inflammatory treatments in the near future. Xianli Yuan, Xiao Peng, Yan Li, and Mingcai Li Copyright © 2015 Xianli Yuan et al. All rights reserved.