Mediators of Inflammation The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Vitamin C Mitigates Oxidative Stress and Tumor Necrosis Factor-Alpha in Severe Community-Acquired Pneumonia and LPS-Induced Macrophages Mon, 01 Sep 2014 11:22:49 +0000 Oxidative stress is an important part of host innate immune response to foreign pathogens. However, the impact of vitamin C on oxidative stress and inflammation remains unclear in community-acquired pneumonia (CAP). We aimed to determine the effect of vitamin C on oxidative stress and inflammation. CAP patients were enrolled. Reactive oxygen species (ROS), DNA damage, superoxide dismutases (SOD) activity, tumor necrosis factor-alpha (TNF-α), and IL-6 were analyzed in CAP patients and LPS-stimulated macrophages cells. MH-S cells were transfected with RFP-LC3 plasmids. Autophagy was measured in LPS-stimulated macrophages cells. Severe CAP patients showed significantly increased ROS, DNA damage, TNF-α, and IL-6. SOD was significantly decreased in severe CAP. Vitamin C significantly decreased ROS, DNA damage, TNF-α, and IL-6. Vitamin C inhibited LPS-induced ROS, DNA damage, TNF-α, IL-6, and p38 in macrophages cells. Vitamin C inhibited autophagy in LPS-induced macrophages cells. These findings indicated that severe CAP exhibited significantly increased oxidative stress, DNA damage, and proinflammatory mediator. Vitamin C mitigated oxidative stress and proinflammatory mediator suggesting a possible mechanism for vitamin C in severe CAP. Yuanyuan Chen, Guangyan Luo, Jiao Yuan, Yuanyuan Wang, Xiaoqiong Yang, Xiaoyun Wang, Guoping Li, Zhiguang Liu, and Nanshan Zhong Copyright © 2014 Yuanyuan Chen et al. All rights reserved. Dendritic Cells from Aged Subjects Display Enhanced Inflammatory Responses to Chlamydophila pneumoniae Mon, 01 Sep 2014 07:53:10 +0000 Chlamydophila pneumoniae (CPn) is a common respiratory pathogen that causes a chronic and persistent airway infection. The elderly display an increased susceptibility and severity to this infection. However, the underlying mechanisms are not well understood. Dendritic cells (DCs) are the initiators and regulators of immune responses. Therefore, we investigated the role of DCs in the age-associated increased CPn infection in vitro in humans. Though the expression of activation markers was comparable between the two age groups, DCs from aged subjects secreted enhanced levels of proinflammatory mediators such as TNF- and CXCL-10 in response to CPn. In contrast, the secretion of IL-10 and innate interferons, IFN- and IFN-, was severely impaired in DCs from aged donors. The increased activation of DCs from aged subjects to CPn also resulted in enhanced proliferation of CD4 and CD8 T cells in a DC-T coculture. Furthermore, T cells primed with CPn-stimulated DCs from aged subjects secreted increased levels of IFN- and reduced levels of IL-10 compared to DCs obtained from young subjects. In summary, DCs from the elderly displayed enhanced inflammatory response to CPn which may result in airway remodeling and increase the susceptibility of the elderly to respiratory diseases such as asthma. Sangeetha Prakash, Sudhanshu Agrawal, Dandan Ma, Sudhir Gupta, Ellena M. Peterson, and Anshu Agrawal Copyright © 2014 Sangeetha Prakash et al. All rights reserved. The Antimicrobial Peptide Lysozyme Is Induced after Multiple Trauma Sun, 31 Aug 2014 11:20:58 +0000 The antimicrobial peptide lysozyme is an important factor of innate immunity and exerts high potential of antibacterial activity. In the present study we evaluated the lysozyme expression in serum of multiple injured patients and subsequently analyzed their possible sources and signaling pathways. Expression of lysozyme was examined in blood samples of multiple trauma patients from the day of trauma until 14 days after trauma by ELISA. To investigate major sources of lysozyme, its expression and regulation in serum samples, different blood cells, and tissue samples were analysed by ELISA and real-time PCR. Neutrophils and hepatocytes were stimulated with cytokines and supernatant of Staphylococcus aureus. The present study demonstrates the induction and release of lysozyme in serum of multiple injured patients. The highest lysozyme expression of all tested cells and tissues was detected in neutrophils. Stimulation with trauma-related factors such as interleukin-6 and S. aureus induced lysozyme expression. Liver tissue samples of patients without trauma show little lysozyme expression compared to neutrophils. After stimulation with bacterial fragments, lysozyme expression of hepatocytes is upregulated significantly. Toll-like receptor 2, a classic receptor of Gram-positive bacterial protein, was detected as a possible target for lysozyme induction. Tim Klüter, Stefanie Fitschen-Oestern, Sebastian Lippross, Matthias Weuster, Rolf Mentlein, Nadine Steubesand, Claudia Neunaber, Frank Hildebrand, Thomas Pufe, Mersedeh Tohidnezhad, Andreas Beyer, Andreas Seekamp, and Deike Varoga Copyright © 2014 Tim Klüter et al. All rights reserved. Synergistic Effect of Vaginal Trauma and Ovariectomy in a Murine Model of Stress Urinary Incontinence: Upregulation of Urethral Nitric Oxide Synthases and Estrogen Receptors Sun, 31 Aug 2014 09:16:19 +0000 The molecular mechanisms underlying stress urinary incontinence (SUI) are unclear. We aimed to evaluate the molecular alterations in mice urethras following vaginal trauma and ovariectomy (OVX). Twenty-four virgin female mice were equally distributed into four groups: noninstrumented control; vaginal distension (VD) group; OVX group; and VD + OVX group. Changes in leak point pressures (LPPs), genital tract morphology, body weight gain, plasma 17β-estradiol level and expressions of neuronal nitric oxide synthase (nNOS), induced nitric oxide synthase (iNOS), and estrogen receptors (ERs—ERα and ERβ) were analyzed. Three weeks after VD, the four groups differed significantly in genital size and body weight gain. Compared with the control group, the plasma estradiol levels were significantly decreased in the OVX and VD + OVX groups, and LPPs were significantly decreased in all three groups. nNOS, iNOS, and ERα expressions in the urethra were significantly increased in the VD and VD + OVX groups, whereas ERβ expression was significantly increased only in the VD + OVX group. These results show that SUI following vaginal trauma and OVX involves urethral upregulations of nNOS, iNOS, and ERs, suggesting that NO- and ER-mediated signaling might play a role in the synergistic effect of birth trauma and OVX-related SUI pathogenesis. Huey-Yi Chen, Wen-Chi Chen, Yu-Ning Lin, and Yung-Hsiang Chen Copyright © 2014 Huey-Yi Chen et al. All rights reserved. Nutritional Recovery Promotes Hypothalamic Inflammation in Rats during Adulthood Sun, 31 Aug 2014 07:49:03 +0000 We evaluated whether protein restriction in fetal life alters food intake and glucose homeostasis in adulthood by interfering with insulin signal transduction through proinflammatory mechanisms in the hypothalamus and peripheral tissues. Rats were divided into the following: a control group (C); a recovered group (R); and a low protein (LP) group. Relative food intake was greater and serum leptin was diminished in LP and R compared to C rats. Proinflammatory genes and POMC mRNA were upregulated in the hypothalamus of R group. Hypothalamic NPY mRNA expression was greater but AKT phosphorylation was diminished in the LP than in the C rats. In muscle, AKT phosphorylation was higher in restricted than in control animals. The HOMA-IR was decreased in R and C compared to the LP group. In contrast, the Kitt in R was similar to that in C and both were lower than LP rats. Thus, nutritional recovery did not alter glucose homeostasis but produced middle hyperphagia, possibly due to increased anorexigenic neuropeptide expression that counteracted the hypothalamic inflammatory process. In long term protein deprived rats, hyperphagia most likely resulted from increased orexigenic neuropeptide expression, and glucose homeostasis was maintained, at least in part, at the expense of increased muscle insulin sensitivity. Hellen Barbosa Farias Silva, Ana Paula Carli de Almeida, Katarine Barbosa Cardoso, Letícia Martins Ignacio-Souza, Silvia Regina de Lima Reis, Marise Auxiliadora de Barros Reis, Márcia Queiroz Latorraca, Marciane Milanski, and Vanessa Cristina Arantes Copyright © 2014 Hellen Barbosa Farias Silva et al. All rights reserved. Calpain Activity and Toll-Like Receptor 4 Expression in Platelet Regulate Haemostatic Situation in Patients Undergoing Cardiac Surgery and Coagulation in Mice Sun, 31 Aug 2014 07:00:21 +0000 Human platelets express Toll-like receptors (TLR) 4. However, the mechanism by which TLR4 directly affects platelet aggregation and blood coagulation remains to be explored. Therefore, in this study, we evaluated the platelet TLR4 expression in patients who underwent CABG surgery; we explored the correlation between platelet TLR4 expression and the early outcomes in hospital of patients. Additionally, C57BL/6 and C57BL/6-TlrLPS−/− mice were used to explore the roles of platelet TLR4 in coagulation by platelet aggregometry and rotation thromboelastometry. In conclusion, our results highlight the important roles of TLR4 in blood coagulation and platelet function. Of clinical relevance, we also explored novel roles for platelet TLR4 that are associated with early outcomes in cardiac surgery. Jui-Chi Tsai, Yi-Wen Lin, Chun-Yao Huang, Feng-Yen Lin, and Chien-Sung Tsai Copyright © 2014 Jui-Chi Tsai et al. All rights reserved. Unraveling the Complex Relationship Triad between Lipids, Obesity, and Inflammation Thu, 28 Aug 2014 08:41:12 +0000 Obesity today stands at the intersection between inflammation and metabolic disorders causing an aberration of immune activity, and resulting in increased risk for diabetes, atherosclerosis, fatty liver, and pulmonary inflammation to name a few. Increases in mortality and morbidity in obesity related inflammation have initiated studies to explore different lipid mediated molecular pathways of attempting resolution that uncover newer therapeutic opportunities of anti-inflammatory components. Majorly the thromboxanes, prostaglandins, leukotrienes, lipoxins, and so forth form the group of lipid mediators influencing inflammation. Of special mention are the omega-6 and omega-3 fatty acids that regulate inflammatory mediators of interest in hepatocytes and adipocytes via the cyclooxygenase and lipoxygenase pathways. They also exhibit profound effects on eicosanoid production. The inflammatory cyclooxygenase pathway arising from arachidonic acid is a critical step in the progression of inflammatory responses. New oxygenated products of omega-3 metabolism, namely, resolvins and protectins, behave as endogenous mediators exhibiting powerful anti-inflammatory and immune-regulatory actions via the peroxisome proliferator-activated receptors (PPARs) and G protein coupled receptors (GPCRs). In this review we attempt to discuss the complex pathways and links between obesity and inflammation particularly in relation to different lipid mediators. Shahida A. Khan, Ashraf Ali, Sarah A. Khan, Solafa A. Zahran, Ghazi Damanhouri, Esam Azhar, and Ishtiaq Qadri Copyright © 2014 Shahida A. Khan et al. All rights reserved. Prenatal Exposure to Nicotine in Pregnant Rat Increased Inflammatory Marker in Newborn Rat Thu, 28 Aug 2014 00:00:00 +0000 This study aimed to investigate any inflammatory effect of nicotine on rat embryo by exposing their mothers to different dosages of nicotine during pregnancy. During this experimental study, 32 pregnant healthy Wistar rats were divided into 4 equal groups, including a control and 3 nicotine exposure groups. Injections were performed subcutaneously starting at the first day of pregnancy until parturition. As the dosages of nicotine were increased, the weight gain by pregnant rats and the mean weight of their newborns were significantly reduced. Mean ± SD of hs-CRP was significantly higher among groups exposed to various dosages of nicotine (2, 4, and 6 mg/kg) compared to the control group () and its increasing rate was also dose dependent. Mean ± SD serum level of IL-6 and TNF- among all groups exposed to nicotine, except for 2 mg/kg nicotine injected group, was increased significantly (). Mean ± SD of serum level of TGF- and nitrite oxide among exposure groups showed significant differences compared to the control group only at the dosage of 6 mg/kg (). The current study showed that exposing pregnant rats to nicotine causes a dose dependent increase in the rate of all the studied inflammatory serum markers among their newborns. Yosouf Mohsenzadeh, Asghar Rahmani, Javad Cheraghi, Maryam Pyrani, and Khairollah Asadollahi Copyright © 2014 Yosouf Mohsenzadeh et al. All rights reserved. Dynamics of Acute Local Inflammatory Response after Autologous Transplantation of Muscle-Derived Cells into the Skeletal Muscle Wed, 27 Aug 2014 11:03:25 +0000 The vast majority of myoblasts transplanted into the skeletal muscle die within the first week after injection. Inflammatory response to the intramuscular cell transfer was studied in allogeneic but not in autologous model. The aim of this study was to evaluate immune reaction to autotransplantation of myogenic cells and to assess its dynamics within the first week after injection. Muscle-derived cells or medium alone was injected into the intact skeletal muscles in autologous model. Tissue samples were collected 1, 3, and 7 days after the procedure. Our analysis revealed the peak increase of the gene expression of all evaluated cytokines (Il-1α, Il-1β, Il-6, Tgf-β, and Tnf-α) at day 1. The mRNA level of analyzed cytokines normalized in subsequent time points. The increase of Il-β gene expression was further confirmed at the protein level. Analysis of the tissue sections revealed rapid infiltration of injected cell clusters with neutrophils and macrophages. The inflammatory infiltration was almost completely resolved at day 7. The survived cells were able to participate in the muscle regeneration process. Presented results demonstrate that autotransplanted muscle-derived cells induce classical early immune reaction in the site of injection which may contribute to cellular graft elimination. Anna Burdzinska, Kamila Gala, Cezary Kowalewski, Radosław Zagozdzon, Zdzisław Gajewski, and Leszek Pączek Copyright © 2014 Anna Burdzinska et al. All rights reserved. Tumor Necrosis Factor Induces Developmental Stage-Dependent Structural Changes in the Immature Small Intestine Wed, 27 Aug 2014 09:02:52 +0000 Background. Premature infants are commonly subject to intestinal inflammation. Since the human small intestine does not reach maturity until term gestation, premature infants have a unique challenge, as either acute or chronic inflammation may alter the normal development of the intestinal tract. Tumor necrosis factor (TNF) has been shown to acutely alter goblet cell numbers and villus length in adult mice. In this study we tested the effects of TNF on villus architecture and epithelial cells at different stages of development of the immature small intestine. Methods. To examine the effects of TNF-induced inflammation, we injected acute, brief, or chronic exposures of TNF in neonatal and juvenile mice. Results. TNF induced significant villus blunting through a TNF receptor-1 (TNFR1) mediated mechanism, leading to loss of villus area. This response to TNFR1 signaling was altered during intestinal development, despite constant TNFR1 protein expression. Acute TNF-mediated signaling also significantly decreased Paneth cells. Conclusions. Taken together, the morphologic changes caused by TNF provide insight as to the effects of inflammation on the developing intestinal tract. Additionally, they suggest a mechanism which, coupled with an immature immune system, may help to explain the unique susceptibility of the immature intestine to inflammatory diseases such as NEC. Kathryn S. Brown, Huiyu Gong, Mark R. Frey, Brock Pope, Matthew Golden, Katerina Martin, Mitchel Obey, and Steven J. McElroy Copyright © 2014 Kathryn S. Brown et al. All rights reserved. Lipoprotein Lipase and PPAR Alpha Gene Polymorphisms, Increased Very-Low-Density Lipoprotein Levels, and Decreased High-Density Lipoprotein Levels as Risk Markers for the Development of Visceral Leishmaniasis by Leishmania infantum Wed, 27 Aug 2014 08:13:27 +0000 In visceral leishmaniasis (VL) endemic areas, a minority of infected individuals progress to disease since most of them develop protective immunity. Therefore, we investigated the risk markers of VL within nonimmune sector. Analyzing infected symptomatic and, asymptomatic, and noninfected individuals, VL patients presented with reduced high-density lipoprotein cholesterol (HDL-C), elevated triacylglycerol (TAG), and elevated very-low-density lipoprotein cholesterol (VLDL-C) levels. A polymorphism analysis of the lipoprotein lipase (LPL) gene using HindIII restriction digestion (N = 156 samples) (H+ = the presence and H− = the absence of mutation) revealed an increased adjusted odds ratio (OR) of VL versus noninfected individuals when the H+/H+ was compared with the H−/H− genotype (OR = 21.3; 95% CI = 2.32–3335.3; P = 0.003). The H+/H+ genotype and the H+ allele were associated with elevated VLDL-C and TAG levels (P < 0.05) and reduced HDL-C levels (P < 0.05). An analysis of the L162V polymorphism in the peroxisome proliferator-activated receptor alpha (PPARα) gene (n = 248) revealed an increased adjusted OR when the Leu/Val was compared with the Leu/Leu genotype (OR = 8.77; 95% CI = 1.41–78.70; P = 0.014). High TAG (P = 0.021) and VLDL-C (P = 0.023) levels were associated with susceptibility to VL, whereas low HDL (P = 0.006) levels with resistance to infection. The mutated LPL and the PPARα Leu/Val genotypes may be considered risk markers for the development of VL. Márcia Dias Teixeira Carvalho, Diego Peres Alonso, Célia Maria Vieira Vendrame, Dorcas Lamounier Costa, Carlos Henrique Nery Costa, Guilherme Loureiro Werneck, Paulo Eduardo Martins Ribolla, and Hiro Goto Copyright © 2014 Márcia Dias Teixeira Carvalho et al. All rights reserved. Secretoglobin Superfamily Protein SCGB3A2 Deficiency Potentiates Ovalbumin-Induced Allergic Pulmonary Inflammation Wed, 27 Aug 2014 08:12:05 +0000 Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, which may play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2, Scgb3a2−/− mice were generated and characterized. Scgb3a2−/− mice did not exhibit any overt phenotypes. In ovalbumin- (OVA-) induced airway allergy inflammation model, Scgb3a2−/− mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenic Scgb3a2−/− mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates. These results indicate that the loss of SCGB3A2 function was influenced by a modifier gene(s) in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent. Taketomo Kido, Mitsuhiro Yoneda, Yan Cai, Tsutomu Matsubara, Jerrold M. Ward, and Shioko Kimura Copyright © 2014 Taketomo Kido et al. All rights reserved. Adipose-Derived Stem Cells Ameliorate Allergic Airway Inflammation by Inducing Regulatory T Cells in a Mouse Model of Asthma Tue, 26 Aug 2014 08:44:42 +0000 Although several studies have demonstrated that mesenchymal stem cells derived from adipose tissue (ASCs) can ameliorate allergic airway inflammation, the immunomodulatory mechanism of ASCs remains unclear. In this study, we investigated whether regulatory T cells (Tregs) induction is a potential mechanism in immunomodulatory effects of ASCs on allergic airway disease and how these induced Tregs orchestrate allergic inflammation. Intravenous administration of ASCs significantly reduced allergic symptoms and inhibited eosinophilic inflammation. Airway hyperresponsiveness, total immune cell and eosinophils in the bronchoalveolar lavage fluid, mucus production, and serum allergen-specific IgE and IgG1 were significantly reduced after ASCs administration. ASCs significantly inhibited Th2 cytokines (IL-4, IL-5, and IL-13) and enhanced Th1 cytokine (IFN-γ) and regulatory cytokines (IL-10 and TGF-β) in the bronchoalveolar lavage fluid and lung draining lymph nodes. Furthermore, levels of IDO, TGF-β, and PGE2 were significantly increased after ASCs administration. Interestingly, this upregulation was accompanied by increased Treg populations. In conclusion, ASCs ameliorated allergic airway inflammation and improved lung function through the induction of Treg expansion. The induction of Treg by ASCs involves the secretion of soluble factors such as IDO, TGF-β, and PGE2 and Treg might be involved in the downregulation of Th2 cytokines and upregulation of Th1 cytokines production. Kyu-Sup Cho, Mi-Kyung Park, Shin-Ae Kang, Hee-Young Park, Sung-Lyong Hong, Hye-Kyung Park, Hak-Sun Yu, and Hwan-Jung Roh Copyright © 2014 Kyu-Sup Cho et al. All rights reserved. Response to Statin Therapy in Obstructive Sleep Apnea Syndrome: A Multicenter Randomized Controlled Trial Mon, 25 Aug 2014 10:50:24 +0000 Rationale. Accumulated evidence implicates sympathetic activation as inducing oxidative stress and systemic inflammation, which in turn lead to hypertension, endothelial dysfunction, and atherosclerosis in obstructive sleep apnea (OSA). Statins through their pleiotropic properties may modify inflammation, lipid profile, and cardiovascular outcomes in OSA. Methods. This multicenter, randomized, double-blind study compared the effects of atorvastatin 40 mg/day versus placebo over 12 weeks on endothelial function (the primary endpoint) measured by peripheral arterial tone (PAT). Secondary endpoints included office blood pressure (BP), early carotid atherosclerosis, arterial stiffness measured by pulse wave velocity (PWV), and metabolic parameters. Results. 51 severe OSA patients were randomized. Key demographics for the study population were age 54 ± 11 years, 21.6% female, and BMI 28.5 ± 4.5 kg/m2. In intention to treat analysis, mean PAT difference between atorvastatin and placebo groups was 0.008 (−0.29; 0.28), . Total and LDL cholesterol significantly improved with atorvastatin. Systolic BP significantly decreased with atorvastatin (mean difference: −6.34 mmHg (−12.68; −0.01), ) whereas carotid atherosclerosis and PWV were unchanged compared to the placebo group. Conclusion. In OSA patients, 3 months of atorvastatin neither improved endothelial function nor reduced early signs of atherosclerosis although it lowered blood pressure and improved lipid profile. This trial is registered with NCT00669695. Marie Joyeux-Faure, Renaud Tamisier, Jean-Philippe Baguet, Sonia Dias-Domingos, Stephen Perrig, Georges Leftheriotis, Jean-Paul Janssens, Wojciech Trzepizur, Sandrine H. Launois, Françoise Stanke-Labesque, Patrick A. Lévy, Frédéric Gagnadoux, and Jean-Louis Pepin Copyright © 2014 Marie Joyeux-Faure et al. All rights reserved. The Protective Effects of the Supercritical-Carbon Dioxide Fluid Extract of Chrysanthemum indicum against Lipopolysaccharide-Induced Acute Lung Injury in Mice via Modulating Toll-Like Receptor 4 Signaling Pathway Mon, 25 Aug 2014 09:25:53 +0000 The supercritical-carbon dioxide fluid extract of Chrysanthemum indicum Linné. (CFE) has been demonstrated to be effective in suppressing inflammation. The aim of this study is to investigate the preventive action and underlying mechanisms of CFE on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. ALI was induced by intratracheal instillation of LPS into lung, and dexamethasone was used as a positive control. Results revealed that pretreatment with CFE abated LPS-induced lung histopathologic changes, reduced the wet/dry ratio and proinflammatory cytokines productions (TNF-α, IL-1β, and IL-6), inhibited inflammatory cells migrations and protein leakages, suppressed the levels of MPO and MDA, and upregulated the abilities of antioxidative enzymes (SOD, CAT, and GPx). Furthermore, the pretreatment with CFE downregulated the activations of NF-κB and the expressions of TLR4/MyD88. These results suggested that CFE exerted potential protective effects against LPS-induced ALI in mice and was a potential therapeutic drug for ALI. Its mechanisms were at least partially associated with the modulations of TLR4 signaling pathways. Xiao-Li Wu, Xue-Xuan Feng, Chu-Wen Li, Xiao-Jun Zhang, Zhi-Wei Chen, Jian-Nan Chen, Xiao-Ping Lai, Sai-Xia Zhang, Yu-Cui Li, and Zi-Ren Su Copyright © 2014 Xiao-Li Wu et al. All rights reserved. Consequences of the Lack of CD73 and Prostatic Acid Phosphatase in the Lymphoid Organs Sun, 24 Aug 2014 11:57:37 +0000 CD73, ecto-5′-nucleotidase, is the key enzyme catalyzing the conversion of extracellular AMP to adenosine that controls vascular permeability and immunosuppression. Also prostatic acid phosphatase (PAP) possesses ecto-5′-nucleotidase/AMPase activity and is present in leukocytes. However, its role related to immune system is unknown. Therefore, we analyzed enzymatic activities and leukocyte subtypes of CD73 and PAP knockouts and generated CD73/PAP double knockout mice to elucidate the contribution of CD73 and PAP to immunological parameters. Enzymatic assays confirmed the ability of recombinant human PAP to hydrolyze [3H]AMP, although at much lower rate than human CD73. Nevertheless, 5′-nucleotidase/AMPase activity in splenocytes and lymphocytes from PAP−/− mice tended to be lower than in wild-type controls, suggesting potential contribution of PAP, along with CD73, into lymphoid AMP metabolism ex vivo. Single knockouts had decreased number of regulatory T cells in thymus and CD73/PAP double knockouts exhibited reduced percentages of CD4+ cells in spleen, regulatory T cells in lymph nodes and thymus, and CD4+ and CD8+ cells in blood. These findings suggest that PAP has a synergistic role together with CD73 in the immune system by contributing to the balance of leukocyte subpopulations and especially to the number of regulatory T cells in lymph nodes and thymus. Gennady G. Yegutkin, Kaisa Auvinen, Marika Karikoski, Pia Rantakari, Heidi Gerke, Kati Elima, Mikael Maksimow, Ileana B. Quintero, Pirkko Vihko, Marko Salmi, and Sirpa Jalkanen Copyright © 2014 Gennady G. Yegutkin et al. All rights reserved. TRPV1 Antagonism by Capsazepine Modulates Innate Immune Response in Mice Infected with Plasmodium berghei ANKA Sun, 24 Aug 2014 11:53:23 +0000 Thousands of people suffer from severe malaria every year. The innate immune response plays a determinant role in host’s defence to malaria. Transient receptor potential vanilloid 1 (TRPV1) modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. We investigated the effects of capsazepine, a TRPV1 antagonist, in malaria. C57BL/6 mice received 105 red blood cells infected with Plasmodium berghei ANKA intraperitoneally. Noninfected mice were used as controls. Capsazepine or vehicle was given intraperitoneally for 6 days. Mice were culled on day 7 after infection and blood and spleen cell phenotype and activation were evaluated. Capsazepine decreased circulating but not spleen F4/80+Ly6G+ cell numbers as well as activation of both F4/80+and F4/80+Ly6G+ cells in infected animals. In addition, capsazepine increased circulating but not spleen GR1+ and natural killer (NK) population, without interfering with natural killer T (NKT) cell numbers and blood NK and NKT activation. However, capsazepine diminished CD69 expression in spleen NKT but not NK cells. Infection increased lipid peroxidation and the release of TNFα and IFNγ, although capsazepine-treated group exhibited lower levels of lipid peroxidation and TNFα. Capsazepine treatment did not affect parasitaemia. Overall, TRPV1 antagonism modulates the innate immune response to malaria. Elizabeth S. Fernandes, Carolina X. L. Brito, Simone A. Teixeira, Renato Barboza, Aramys S. dos Reis, Ana Paula S. Azevedo-Santos, Marcelo Muscará, Soraia K. P. Costa, Claudio R. F. Marinho, Susan D. Brain, and Marcos A. G. Grisotto Copyright © 2014 Elizabeth S. Fernandes et al. All rights reserved. Flavocoxid, a Nutraceutical Approach to Blunt Inflammatory Conditions Sun, 24 Aug 2014 09:38:57 +0000 Flavonoids, from Scutellaria baicalensis (Chinese skullcap) and Acacia catechu (black catechu), have been shown to exert a variety of therapeutic effects, including anti-inflammatory, antiviral, antibacterial, and anticancer activities. Flavocoxid is a mixed extract containing baicalin and catechin and it acts as a dual balanced inhibitor of cyclooxygenase-1 (COX-1) and COX-2 peroxidase enzyme activities with a significant inhibition of 5-lipoxygenase (5-LOX) enzyme activity in vitro. Flavocoxid downregulates gene or protein expression of several inflammatory markers and exerts also strong antioxidant activity in several experimental models. Controlled clinical trials and a postmarketing study have clearly shown that flavocoxid is as effective as naproxen in managing the signs and symptoms of osteoarthritis of the knee and it has better upper gastrointestinal, renal, and respiratory safety profile than naproxen. Flavocoxid may therefore provide a potential therapeutic approach to the treatment of chronic inflammatory conditions. Alessandra Bitto, Francesco Squadrito, Natasha Irrera, Gabriele Pizzino, Giovanni Pallio, Anna Mecchio, Federica Galfo, and Domenica Altavilla Copyright © 2014 Alessandra Bitto et al. All rights reserved. Macrophage P2X7 Receptor Function Is Reduced during Schistosomiasis: Putative Role of TGF-β1 Sun, 24 Aug 2014 08:21:06 +0000 Schistosomiasis is a chronic inflammatory disease whose macrophages are involved in immunopathology modulation. Although P2X7 receptor signaling plays an important role in inflammatory responses mediated by macrophages, no reports have examined the role of P2X7 receptors in macrophage function during schistosomiasis. Thus, we evaluated P2X7 receptor function in peritoneal macrophages during schistosomiasis using an ATP-induced permeabilization assay and measurements of the intracellular Ca2+ concentration. ATP treatment induced significantly less permeabilization in macrophages from S. mansoni-infected mice than in control cells from uninfected animals. Furthermore, P2X7-mediated increases in intracellular Ca2+ levels were also reduced in macrophages from infected mice. TGF-β1 levels were increased in the peritoneal cavity of infected animals, and pretreatment of control macrophages with TGF-β1 reduced ATP-induced permeabilization, mimicking the effect of S. mansoni infection. Western blot and qRT-PCR data showed no difference in P2X7 protein and mRNA between uninfected, infected, and TGF-β1-treated groups. However, immunofluorescence analysis revealed reduced cell surface localization of P2X7 receptors in macrophages from infected and TGF-β1-treated mice compared to controls. Therefore, our data suggest that schistosomiasis reduces peritoneal macrophage P2X7 receptor signaling. This effect is likely due to the fact that infected mice have increased levels of TGF-β1, which reduces P2X7 receptor cell surface expression. Suellen D’arc Santos Oliveira, Hayandra Ferreira Nanini, Luiz Eduardo Baggio Savio, Mariana Caldas Waghabi, Claudia Lucia Martins Silva, and Robson Coutinho-Silva Copyright © 2014 Suellen D’arc Santos Oliveira et al. All rights reserved. Inflammation and Growth in Young Children with Obstructive Sleep Apnea Syndrome before and after Adenotonsillectomy Sun, 24 Aug 2014 07:29:56 +0000 Background. Obstructive sleep apnea (OSA) is associated with growth impairment that usually improves following effective treatment. In this study we investigated the mechanisms underlying the growth processes in young children diagnosed with OSA, before and after adenotonsillectomy (T&A). Methods. Young children (6–36 months old) were enrolled and evaluated before and several months after T&A surgery for height, weight, circulating high sensitive C-reactive protein (CRP), and insulin-like growth factor 1 (IGF-1) levels. Caloric intake was assessed by a validated Short Food Frequency Questionnaire (SFFQ). Results. Following T&A, children added 4.81 cm and 1.88 kg to their height and weight, respectively ( for both) and had a significant increase in BMI Z score (). Increased caloric intake of 377 kcal/day was noted (), with increased protein and decreased fat intake. The decrease in CRP levels correlated with the increase in body weight in boys (, adjusted for caloric intake). Conclusions. Adenotonsillectomy results in enhanced somatic growth in young children that correlates with a decrease in systemic inflammation and caloric intake increment. Our findings imply that systemic inflammation may have an important role in this OSA-related morbidity. Yuval Nachalon, Neta Lowenthal, Sari Greenberg-Dotan, and Aviv D. Goldbart Copyright © 2014 Yuval Nachalon et al. All rights reserved. Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability Sun, 24 Aug 2014 00:00:00 +0000 Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective.    rabbit foam cells are more invasive and more prone to apoptosis than    cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction. Jason L. Johnson, Nicholas P. Jenkins, Wei-Chun Huang, Karina Di Gregoli, Graciela B. Sala-Newby, Vincent P. W. Scholtes, Frans L. Moll, Gerard Pasterkamp, and Andrew C. Newby Copyright © 2014 Jason L. Johnson et al. All rights reserved. Effects of Cholinergic Stimulation with Pyridostigmine Bromide on Chronic Chagasic Cardiomyopathic Mice Sun, 24 Aug 2014 00:00:00 +0000 The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido), on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con) or chronically infected (5 months) with Trypanosoma cruzi (chagasic:Chg) were treated or not (NT) with Pyrido for one month. At the end of this period, electrocardiogram (ECG); cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγ with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice. Marília Beatriz de Cuba, Marcus Paulo Ribeiro Machado, Thais Soares Farnesi, Angelica Cristina Alves, Livia Alves Martins, Lucas Felipe de Oliveira, Caroline Santos Capitelli, Camila Ferreira Leite, Marcos Vinícius Silva, Juliana Reis Machado, Henrique Borges Kappel, Helioswilton Sales de Campos, Luciano Paiva, Natália Lins da Silva Gomes, Ana Carolina Guimarães Faleiros, Constança Felicia de Paoli de Carvalho Britto, Wilson Savino, Otacílio Cruz Moreira, Virmondes Rodrigues Jr., Nicola Montano, Eliane Lages-Silva, Luis Eduardo Ramirez, and Valdo Jose Dias da Silva Copyright © 2014 Marília Beatriz de Cuba et al. All rights reserved. The Study of Mechanisms of Protective Effect of Rg1 against Arthritis by Inhibiting Osteoclast Differentiation and Maturation in CIA Mice Thu, 21 Aug 2014 05:47:50 +0000 Ginsenoside Rg1 is a natural product extracted from Panax ginseng C.A. Although Rg1 protects tissue structure and functions by inhibiting local inflammatory reaction, the mechanism remains poorly understood. In vitro, Rg1 dose-dependently inhibited TRAP activity in receptor activator of nuclear factor-κB ligand- (RANKL-) induced osteoclasts and decreased the number of osteoclasts and osteoclast resorption area. Rg1 also significantly inhibited the RANK signaling pathway, including suppressing the expression of Trap, cathepsin K, matrix metalloproteinase 9 (MMP9), and calcitonin receptor (CTR). In vivo, Rg1 dramatically decreased arthritis scores in CIA mice and effectively controlled symptoms of inflammatory arthritis. Pathologic analysis demonstrated that Rg1 significantly attenuated pathological changes in CIA mice. Pronounced reduction in synovial hyperplasia and inflammatory cell invasion were observed in CIA mice after Rg1 therapy. Alcian blue staining results illustrated that mice treated with Rg1 had significantly reduced destruction in the articular cartilage. TRAP and cathepsin K staining results demonstrated a significant reduction of numbers of OCs in the articular cartilage in proximal interphalangeal joints and ankle joints in Rg1-treated mice. In summary, this study revealed that Rg1 reduced the inflammatory destruction of periarticular bone by inhibiting differentiation and maturation of osteoclasts in CIA mice. Yanqing Gu, Weimin Fan, and Guoyong Yin Copyright © 2014 Yanqing Gu et al. All rights reserved. Effect of Th17 and Treg Axis Disorder on Outcomes of Pulmonary Arterial Hypertension in Connective Tissue Diseases Wed, 20 Aug 2014 07:43:16 +0000 This prospective cohort study is to verify the hypothesis that the balance of Th17 and Treg cells frequencies in the peripheral circulation is disturbed in patients with varying degrees of connective tissue diseases-associated pulmonary arterial hypertension (CTD-aPAH) and to prove the influence of Th17/Treg imbalance on prognosis. We detected the frequencies and absolute counts of Th17 and Treg cells and related serum cytokines secretion and expressions of key transcription factors in 117 patients with connective tissue diseases (CTD), 53 patients with CTD-aPAH, and 48 healthy volunteers. Moreover, the median value according to levels of Th17/Treg ratios in patients with CTD-aPAH was chosen as basis of group division for survival analysis. CTD-aPAH patients revealed significant increase in peripheral Th17 cells, Th17-related cytokines, and ROR γt mRNA levels. They also presented a significant decrease in Treg cells, Treg-related cytokines, and Foxp3 mRNA levels as compared with CTD patients and healthy controls. More importantly, the Th17/Treg ratio was significantly related to the severity and prognosis of CTD-aPAH. This study indicated that the Th17/Treg axis disorder plays a critical role in CTD-aPAH. Furthermore, the dynamic balance between Th17 and Treg cells was likely to influence prognosis of patients with CTD-aPAH. Saren Gaowa, Wenyong Zhou, Lilei Yu, Xiaohui Zhou, Kai Liao, Kang Yang, Zhibin Lu, Hong Jiang, and Xiaofeng Chen Copyright © 2014 Saren Gaowa et al. All rights reserved. Metformin Attenuates Experimental Autoimmune Arthritis through Reciprocal Regulation of Th17/Treg Balance and Osteoclastogenesis Wed, 20 Aug 2014 07:11:29 +0000 Metformin is widely used to suppress certain functions of the cells found in diseases including diabetes and obesity. In this study, the effects of metformin on downregulating IL-17-producing T (Th17) cells, activating and upregulating regulatory T (Treg) cells, suppressing osteoclastogenesis, and clinically scoring collagen-induced arthritis (CIA) were investigated. To evaluate the effect of metformin on CIA, mice were orally fed with either metformin or saline as control three times a week for nine weeks. Histological analysis of the joints was performed using immunohistochemistry and Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. Metformin mitigated the severity of CIA, reduced serum immunoglobulin concentrations, and reciprocally regulated Th17/Treg axis. Also, metformin treatment of normal cells cultured in Th17 conditions decreased the number of Th17 cells and increased the number of Treg cells. Metformin decreased gene expression and osteoclastogenic activity in CIA and normal mice. These results indicate that metformin had immunomodulatory actions influencing anti-inflammatory action on CIA through the inhibition of Th17 cell differentiation and the upregulation of Treg cell differentiation along with the suppression of osteoclast differentiation. Our results suggest that metformin may be a potential therapeutic for rheumatoid arthritis. Hye-Jin Son, Jennifer Lee, Seon-Yeong Lee, Eun-Kyung Kim, Min-Jung Park, Kyoung-Woon Kim, Sung-Hwan Park, and Mi-La Cho Copyright © 2014 Hye-Jin Son et al. All rights reserved. Hydrogen-Rich Saline Inhibits NLRP3 Inflammasome Activation and Attenuates Experimental Acute Pancreatitis in Mice Wed, 20 Aug 2014 06:32:33 +0000 Increasing evidence has demonstrated that reactive oxygen species (ROS) induces oxidative stress and plays a crucial role in the pathogenesis of acute pancreatitis (AP). Hydrogen-rich saline (HRS), a well-known ROS scavenger, has been shown to possess therapeutic benefit on AP in many animal experiments. Recent findings have indicated that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, an intracellular multiprotein complex required for the maturation of interleukin- (IL-) 1β, may probably be a potential target of HRS in the treatment of AP. Therefore, in this study, we evaluated the activation of NLRP3 inflammasome and meanwhile assessed the degree of oxidative stress and inflammatory cascades, as well as the histological alterations in mice suffering from cerulein-induced AP after the treatment of HRS. The results showed that the activation of NLRP3 inflammasome in AP mice was substantially inhibited following the administration of HRS, which was paralleled with the decreased NF-κB activity and cytokines production, attenuated oxidative stress and the amelioration of pancreatic tissue damage. In conclusion, our study has, for the first time, revealed that inhibition of the activation of NLRP3 inflammasome probably contributed to the therapeutic potential of HRS in AP. Jian-Dong Ren, Jie Ma, Jun Hou, Wen-Jin Xiao, Wei-Hua Jin, Juan Wu, and Kai-Hua Fan Copyright © 2014 Jian-Dong Ren et al. All rights reserved. Chagas Disease Cardiomyopathy: Immunopathology and Genetics Tue, 19 Aug 2014 10:56:07 +0000 Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects ca. 10 million people worldwide. About 30% of Chagas disease patients develop chronic Chagas disease cardiomyopathy (CCC), a particularly lethal inflammatory cardiomyopathy that occurs decades after the initial infection, while most patients remain asymptomatic. Mortality rate is higher than that of noninflammatory cardiomyopathy. CCC heart lesions present a Th1 T-cell-rich myocarditis, with cardiomyocyte hypertrophy and prominent fibrosis. Data suggest that the myocarditis plays a major pathogenetic role in disease progression. Major unmet goals include the thorough understanding of disease pathogenesis and therapeutic targets and identification of prognostic genetic factors. Chagas disease thus remains a neglected disease, with no vaccines or antiparasitic drugs proven efficient in chronically infected adults, when most patients are diagnosed. Both familial aggregation of CCC cases and the fact that only 30% of infected patients develop CCC suggest there might be a genetic component to disease susceptibility. Moreover, previous case-control studies have identified some genes associated to human susceptibility to CCC. In this paper, we will review the immunopathogenesis and genetics of Chagas disease, highlighting studies that shed light on the differential progression of Chagas disease patients to CCC. Edecio Cunha-Neto and Christophe Chevillard Copyright © 2014 Edecio Cunha-Neto and Christophe Chevillard. All rights reserved. α-Lipoic Acid Inhibits Helicobacter pylori-Induced Oncogene Expression and Hyperproliferation by Suppressing the Activation of NADPH Oxidase in Gastric Epithelial Cells Tue, 19 Aug 2014 08:52:56 +0000 Hyperproliferation and oncogene expression are observed in the mucosa of Helicobacter pylori- (H. pylori-) infected patients with gastritis or adenocarcinoma. Expression of oncogenes such as β-catenin and c-myc is related to oxidative stress. α-Lipoic acid (α-LA), a naturally occurring thiol compound, acts as an antioxidant and has an anticancer effect. The aim of this study is to investigate the effect of α-LA on H. pylori-induced hyperproliferation and oncogene expression in gastric epithelial AGS cells by determining cell proliferation (viable cell numbers, thymidine incorporation), levels of reactive oxygen species (ROS), NADPH oxidase activation (enzyme activity, subcellular levels of NADPH oxidase subunits), activation of redox-sensitive transcription factors (NF-κB, AP-1), expression of oncogenes (β-catenin, c-myc), and nuclear localization of β-catenin. Furthermore, we examined whether NADPH oxidase mediates oncogene expression and hyperproliferation in H. pylori-infected AGS cells using treatment of diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase. As a result, α-LA inhibited the activation of NADPH oxidase and, thus, reduced ROS production, resulting in inhibition on activation of NF-κB and AP-1, induction of oncogenes, nuclear translocation of β-catenin, and hyperproliferation in H. pylori-infected AGS cells. DPI inhibited H. pylori-induced activation of NF-κB and AP-1, oncogene expression and hyperproliferation by reducing ROS levels in AGS cells. In conclusion, we propose that inhibiting NADPH oxidase by α-LA could prevent oncogene expression and hyperproliferation occurring in H. pylori-infected gastric epithelial cells. Eunyoung Byun, Joo Weon Lim, Jung Mogg Kim, and Hyeyoung Kim Copyright © 2014 Eunyoung Byun et al. All rights reserved. Age-Related Macular Degeneration in the Aspect of Chronic Low-Grade Inflammation (Pathophysiological ParaInflammation) Tue, 19 Aug 2014 08:32:38 +0000 The products of oxidative stress trigger chronic low-grade inflammation (pathophysiological parainflammation) process in AMD patients. In early AMD, soft drusen contain many mediators of chronic low-grade inflammation such as C-reactive protein, adducts of the carboxyethylpyrrole protein, immunoglobulins, and acute phase molecules, as well as the complement-related proteins C3a, C5a, C5, C5b-9, CFH, CD35, and CD46. The complement system, mainly alternative pathway, mediates chronic autologous pathophysiological parainflammation in dry and exudative AMD, especially in the Y402H gene polymorphism, which causes hypofunction/lack of the protective complement factor H (CFH) and facilitates chronic inflammation mediated by C-reactive protein (CRP). Microglial activation induces photoreceptor cells injury and leads to the development of dry AMD. Many autoantibodies (antibodies against alpha beta crystallin, alpha-actinin, amyloid, C1q, chondroitin, collagen I, collagen III, collagen IV, elastin, fibronectin, heparan sulfate, histone H2A, histone H2B, hyaluronic acid, laminin, proteoglycan, vimentin, vitronectin, and aldolase C and pyruvate kinase M2) and overexpression of Fcc receptors play role in immune-mediated inflammation in AMD patients and in animal model. Macrophages infiltration of retinal/choroidal interface acts as protective factor in early AMD (M2 phenotype macrophages); however it acts as proinflammatory and proangiogenic factor in advanced AMD (M1 and M2 phenotype macrophages). Małgorzata Nita, Andrzej Grzybowski, Francisco J. Ascaso, and Valentín Huerva Copyright © 2014 Małgorzata Nita et al. All rights reserved. Feed-Forward Inhibition of CD73 and Upregulation of Adenosine Deaminase Contribute to the Loss of Adenosine Neuromodulation in Postinflammatory Ileitis Tue, 19 Aug 2014 07:16:37 +0000 Purinergic signalling is remarkably plastic during gastrointestinal inflammation. Thus, selective drugs targeting the “purinome” may be helpful for inflammatory gastrointestinal diseases. The myenteric neuromuscular transmission of healthy individuals is fine-tuned and controlled by adenosine acting on excitatory receptors. Here, we investigated the neuromodulatory role of adenosine in TNBS-inflamed longitudinal muscle-myenteric plexus of the rat ileum. Seven-day postinflammation ileitis lacks adenosine neuromodulation, which may contribute to acceleration of gastrointestinal transit. The loss of adenosine neuromodulation results from deficient accumulation of the nucleoside at the myenteric synapse despite the fact that the increases in ATP release were observed. Disparity between ATP outflow and adenosine deficit in postinflammatory ileitis is ascribed to feed-forward inhibition of ecto-5′-nucleotidase/CD73 by high extracellular ATP and/or ADP. Redistribution of NTPDase2, but not of NTPDase3, from ganglion cell bodies to myenteric nerve terminals leads to preferential ADP accumulation from released ATP, thus contributing to the prolonged inhibition of muscle-bound ecto-5′-nucleotidase/CD73 and to the delay of adenosine formation at the inflamed neuromuscular synapse. On the other hand, depression of endogenous adenosine accumulation may also occur due to enhancement of adenosine deaminase activity. Both membrane-bound and soluble forms of ecto-5′-nucleotidase/CD73 and adenosine deaminase were detected in the inflamed myenteric plexus. These findings provide novel therapeutic targets for inflammatory gut motility disorders. Cátia Vieira, Maria Teresa Magalhães-Cardoso, Fátima Ferreirinha, Isabel Silva, Ana Sofia Dias, Julie Pelletier, Jean Sévigny, and Paulo Correia-de-Sá Copyright © 2014 Cátia Vieira et al. All rights reserved.