International Journal of Inflammation The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Cytokines Modulate the “Immune-Metabolism” Interactions during Behçet Disease: Effect on Arginine Metabolism Tue, 27 Jan 2015 12:00:41 +0000 Aim and Methods. In this study, we evaluated NOS and arginase activities and their regulation during Behçet disease, a systemic chronic inflammatory disorder with uncertain etiology. The peripheral blood mononuclear cells of 36 patients and 15 control samples (PBMC) were cultured in either RPMI 1640, MEM, or DMEM complemented with 10% of FBS and antibiotics. Cultures were performed with or without the control or patients plasma. Subsequent treatment contained anticytokines (IL-6, TGF-β), a mitogenic effector (PHA), or NOS modulators (L-NMMA, BH4). Culture supernatants were harvested after 24 h of incubation. NO and urea measurements were, respectively, performed by modified Griess and Berthelot methods. Results. Higher urea levels were found in patients’ plasma compared to the control’s (P < 0.05). NOS modulators induced inverted production profiles for NO and urea (P < 0.05). Their results differed depending on the clinical findings (P < 0.05). It was also found that cytokine neutralization induced different response profiles in patients as opposed to control cultures (P < 0.05). Conclusion. Our results suggest that arginases can compete with NOS2 for L-arginine during Behçet disease. Both enzymes are regulated by environmental cytokines and substrate availability. Furthermore, it seems that NOS/arginase balance is dependent on clinical expression. Houda Belguendouz, Karima Lahmar-Belguendouz, Djamel Messaoudene, Zineb Djeraba, Fifi Otmani, Djennat Hakem, Ouided S. Lahlou-Boukoffa, Pierre Youinou, and Chafia Touil-Boukoffa Copyright © 2015 Houda Belguendouz et al. All rights reserved. Vasospasm in Cerebral Inflammation Mon, 29 Dec 2014 13:40:51 +0000 All forms of cerebral inflammation as found in bacterial meningitis, cerebral malaria, brain injury, and subarachnoid haemorrhage have been associated with vasospasm of cerebral arteries and arterioles. Vasospasm has been associated with permanent neurological deficits and death in subarachnoid haemorrhage and bacterial meningitis. Increased levels of interleukin-1 may be involved in vasospasm through calcium dependent and independent activation of the myosin light chain kinase and release of the vasoconstrictor endothelin-1. Another key factor in the pathogenesis of cerebral arterial vasospasm may be the reduced bioavailability of the vasodilator nitric oxide. Therapeutic trials in vasospasm related to inflammation in subarachnoid haemorrhage in humans showed a reduction of vasospasm through calcium antagonists, endothelin receptor antagonists, statins, and plasminogen activators. Combination of therapeutic modalities addressing calcium dependent and independent vasospasm, the underlying inflammation, and depletion of nitric oxide simultaneously merit further study in all conditions with cerebral inflammation in double blind randomised placebo controlled trials. Auxiliary treatment with these agents may be able to reduce ischemic brain injury associated with neurological deficits and increased mortality. Michael Eisenhut Copyright © 2014 Michael Eisenhut. All rights reserved. Anti-Inflammatory and Antiarthritic Activity of Anthraquinone Derivatives in Rodents Wed, 24 Dec 2014 00:10:05 +0000 Aloe emodin is isolated compound of aloe vera which is used traditionally as an anti-inflammatory agent. In vitro pharmacokinetic data suggest that glucuronosyl or sulfated forms of aloe emodin may provide some limitations in its absorption capacity. Aloe emodin was reported to have in vitro anti-inflammatory activity due to inhibition of inducible nitric oxide (iNO) and prostaglandin E2, via its action on murine macrophages. However, present work evidenced that molecular docking of aloe emodin modulates the anti-inflammatory activity, as well as expression of COX-2 (cyclooxygenase-2) in rodent. The AEC (4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2 carboxylic acid) was synthesized using aloe emodin as starting material. The study was planned for evaluation of possible anti-inflammatory and antiarthritic activity in carrageenan rat induced paw oedema and complete Freund’s adjuvant induced arthritis in rats. The AE (aloe emodin) and AEC significantly reduced carrageenan induced paw edema at 50 and 75 mg/kg. Complete Freund’s adjuvant induced arthritis model showed significant decrease in injected and noninjected paw volume, arthritic score. AE and AEC showed significant effect on various biochemical, antioxidant, and hematological parameters. Diclofenac sodium 10 mg/kg showed significant inhibition in inflammation and arthritis. Ajay D. Kshirsagar, Prashant V. Panchal, Uday N. Harle, Rabindra K. Nanda, and Haidarali M. Shaikh Copyright © 2014 Ajay D. Kshirsagar et al. All rights reserved. Distinct Lysosome Phenotypes Influence Inflammatory Function in Peritoneal and Bone Marrow-Derived Macrophages Tue, 23 Dec 2014 06:52:47 +0000 Lysosomes play a critical role in the degradation of both extracellular and intracellular material. These dynamic organelles also contribute to nutrient sensing and cell signaling pathways. Macrophages represent a heterogeneous group of phagocytic cells that contribute to tissue homeostasis and inflammation. Recently, there has been a renewed interest in understanding the role of macrophage autophagy and lysosome function in health and disease. Thioglycollate-elicited peritoneal and bone marrow-derived macrophages are commonly used ex vivo systems to study primary macrophage function. In this study, we reveal dramatic baseline differences in the lysosome morphology and function between these macrophage populations and provide evidence that these differences can be functionally relevant. Our results provide important insights into the diversity of lysosomes in primary macrophages and illustrate the importance of accounting for this in data interpretation. Kassandra Weber and Joel D. Schilling Copyright © 2014 Kassandra Weber and Joel D. Schilling. All rights reserved. Follistatin Alleviates Synovitis and Articular Cartilage Degeneration Induced by Carrageenan Tue, 09 Dec 2014 06:55:33 +0000 Activins are proinflammatory cytokines which belong to the TGFβ superfamily. Follistatin is an extracellular decoy receptor for activins. Since both activins and follistatin are expressed in articular cartilage, we hypothesized that activin-follistatin signaling participates in the process of joint inflammation and cartilage degeneration. To test this hypothesis, we examined the effects of follistatin in a carrageenan-induced mouse arthritis model. Synovitis induced by intra-articular injection of carrageenan was significantly alleviated by preinjection with follistatin. Macrophage infiltration into the synovial membrane was significantly reduced in the presence of follistatin. In addition, follistatin inhibited proteoglycan erosion induced by carrageenan in articular cartilage. These data indicate that activin-follistatin signaling is involved in joint inflammation and cartilage homeostasis. Our data suggest that follistatin can be a new therapeutic target for inflammation-induced articular cartilage degeneration. Jun Yamada, Kunikazu Tsuji, Kazumasa Miyatake, Yu Matsukura, Kahaer Abula, Makiko Inoue, Ichiro Sekiya, and Takeshi Muneta Copyright © 2014 Jun Yamada et al. All rights reserved. Hemoglobin Expression in Nonerythroid Cells: Novel or Ubiquitous? Wed, 05 Nov 2014 11:37:13 +0000 Hemoglobin (Hb) is a major protein involved in transport of oxygen (O2). Red blood cells (RBCs) contain maximum amount of Hb and because of their unique structure and plasticity they transport O2 to various tissues of the body at an optimal concentration. Recently, it has been reported that, apart from RBCs, Hb is also expressed by nonerythroid cells such as epithelial cells of different origin. The cells expressing Hb are from the tissues where maintenance of O2 homeostasis is of paramount importance. Hb expression has been observed in the epithelial cells from human tissues including lungs, neurons, retina, and endometrium. Our group has recently demonstrated that Hb is expressed by the cervicovaginal epithelial cells. We further showed that, apart from maintaining O2 homeostasis, Hb and the peptides derived from it play an indispensable role in the protection of vaginal epithelium by exhibiting antimicrobial activity. In this review, we discuss the significance of Hb expression in vaginal epithelial cells and its role in the recognition of pathogens thereby reducing the risk and/or severity of inflammation and/or infections and the possible mechanism by which Hb exhibits antimicrobial and antioxidative functions. Debarchana Saha, Mandar Patgaonkar, Ankit Shroff, Kanchana Ayyar, Tahir Bashir, and K. V. R. Reddy Copyright © 2014 Debarchana Saha et al. All rights reserved. Macrophage Derived Platelet Activating Factor Implicated in the Resolution Phase of Gouty Inflammation Wed, 24 Sep 2014 11:07:43 +0000 Human blood derived in vitro differentiated monocytes or macrophages are a population of cells which have been investigated over the years to determine the role these cells play in the resolution phase of gout. Macrophages are able to phagocytose monosodium urate monohydrate (MSU) crystals without releasing inflammatory factors. This study analysed macrophage platelet activating factor secretion and its possible role in the pathway of gout resolution. Analysis of sunatants from in vitro differentiated macrophages stimulated with MSU crystals revealed the secretion of platelet activating factor (PAF) mean ± SEM; ng/mL per 106 cells. This secretion was absent in immature monocytes treated similarly. When these monocytes were pretreated with recombinant human PAF-acetylhydrolase (rhuPAF-AH) and MSU crystals resulted in TNFα suppression. Addition of WEB2086, a platelet activating factor (PAF) antagonist, to differentiated macrophages with MSU crystals unmasked TNFα secretion mean ± SEM; ng/mL per 106 cells. This study identifies a role for PAF and the PAF receptor antagonist in the pathway by which macrophages ingest MSU crystals and resolve the concomitant inflammation. Darshna Yagnik Copyright © 2014 Darshna Yagnik. All rights reserved. Obesity Related Alterations in Plasma Cytokines and Metabolic Hormones in Chimpanzees Thu, 18 Sep 2014 00:00:00 +0000 Obesity is characterized by chronic low-grade inflammation and serves as a major risk factor for hypertension, coronary artery disease, dyslipidemias, and type-2 diabetes. The purpose of this study was to examine changes in metabolic hormones, inflammatory cytokines, and immune function, in lean, overweight, and obese chimpanzees in a controlled environment. We observed increased plasma circulating levels of proinflammatory TH-1 cytokines, Interferon gamma, interleukin-6, interleukin-12p40, tumor necrosis factor, soluble CD40 ligand, and Interleukin-1β and anti-inflammatory TH-2 cytokines, Interleukin-4, Interleukin-RA, Interleukin-10, and Interleukin-13 in overweight and obese chimpanzees. We also observed increased levels of metabolic hormones glucagon-like-peptide-1, glucagon, connecting peptide, insulin, pancreatic peptide YY3–36, and leptin in the plasma of overweight and obese chimpanzees. Chemokine, eotaxin, fractalkine, and monocyte chemoattractant protein-1 were higher in lean compared to obese chimpanzees, while chemokine ligand 8 increased in plasma of obese chimpanzees. We also observed an obesity-related effect on immune function as demonstrated by lower mitogen induced proliferation, and natural killer activity and higher production of IFN-γ by PBMC in Elispot assay, These findings suggest that lean, overweight, and obese chimpanzees share circulating inflammatory cytokines and metabolic hormone levels with humans and that chimpanzees can serve as a useful animal model for human studies. Pramod Nehete, Elizabeth R. Magden, Bharti Nehete, Patrick W. Hanley, and Christian R. Abee Copyright © 2014 Pramod Nehete et al. All rights reserved. Live Combined Bacillus subtilis and Enterococcus faecium Ameliorate Murine Experimental Colitis by Immunosuppression Mon, 08 Sep 2014 00:00:00 +0000 Live combined Bacillus subtilis and Enterococcus faecium ameliorate murine experimental colitis by immunosuppression manifested by downregulation of TLRs, macrophages, Th1, and Th2 but upregulation of Tregs. S. Chen, Y. Fu, L. L. Liu, W. Gao, Y. L. Liu, S. H. Fei, Y. Tan, and K. F. Zou Copyright © 2014 S. Chen et al. All rights reserved. Contradictory Immune Response in Post Liver Transplantation Hepatitis B and C Sun, 24 Aug 2014 09:21:56 +0000 Hepatitis B and C often progress to decompensated liver cirrhosis requiring orthotopic liver transplantation (OLT). After OLT, hepatitis B recurrence is clinically controlled with a combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues. Another approach is to induce self-producing anti-hepatitis B virus (HBV) antibodies using a HBV envelope antigen vaccine. Patients who had not been HBV carriers such as acutely infected liver failure or who received liver from HBV self-limited donor are good candidate. For chronic HBV carrier patients, a successful response can only be achieved in selected patients such as those treated with experimentally reduced immunosuppression protocols or received an anti-HBV adaptive memory carrying donor liver. Hepatitis C virus (HCV) reinfects transplanted livers at a rate of >90%. HCV reinfected patients show different severities of hepatitis, from mild and slowly progressing to severe and rapidly progressing, possibly resulting from different adaptive immune responses. More than half the patients require interferon treatment, although the success rate is low and carries risks for leukocytopenia and rejection. Managing the immune response has an important role in controlling recurrent hepatitis C. This study aimed to review the adaptive immune response in post-OLT hepatitis B and C. Akinobu Takaki, Takahito Yagi, and Kazuhide Yamamoto Copyright © 2014 Akinobu Takaki et al. All rights reserved. Anti-Inflammatory Effect of Emblica officinalis in Rodent Models of Acute and Chronic Inflammation: Involvement of Possible Mechanisms Thu, 21 Aug 2014 07:10:15 +0000 Emblica officinalis, commonly known as amla in Ayurveda, is unarguably the most important medicinal plant for prevention and treatment of various ailments. The present study investigated the anti-inflammatory activity of hydroalcoholic extract of Emblica officinalis (HAEEO). Acute inflammation in rats was induced by the subplantar injection of carrageenan, histamine, serotonin, and prostaglandin E2 and chronic inflammation was induced by the cotton pellet granuloma. Intraperitoneal (i.p.) administration of HAEEO at all the tested doses (300, 500, and 700 mg/kg) significantly inhibited rat paw edema against all phlogistic agents and also reduced granuloma formation. However, at the dose of 700 mg/kg, HAEEO exhibited maximum anti-inflammatory activity in all experimental models, and the effects were comparable to that of the standard anti-inflammatory drugs. Additionally, in paw tissue the antioxidant activity of HAEEO was also measured and it was found that HAEEO significantly increased glutathione, superoxide dismutase, and catalase activity and subsequently reduced lipid peroxidation evidenced by reduced malondialdehyde. Taken all together, the results indicated that HAEEO possessed potent anti-inflammatory activity and it may hold therapeutic promise in the management of acute and chronic inflammatory conditions. Mahaveer Golechha, Vikas Sarangal, Shreesh Ojha, Jagriti Bhatia, and Dharmveer S. Arya Copyright © 2014 Mahaveer Golechha et al. All rights reserved. Neurotensin Decreases the Proinflammatory Status of Human Skin Fibroblasts and Increases Epidermal Growth Factor Expression Mon, 11 Aug 2014 06:28:10 +0000 Fibroblasts colonization into injured areas during wound healing (WH) is responsible for skin remodelling and is also involved in the modulation of inflammation, as fibroblasts are immunologically active. Herein, we aimed to determine neurotensin effect on the immunomodulatory profile of fibroblasts, both in homeostatic and inflammatory conditions. Neurotensin mediated responses occurred through NTR1 or NTR3 receptors, while under inflammatory conditions NTR1 expression increase seemed to modulate neurotensin responses. Among different immunomodulatory genes, CCL11, IL-8, and IL-6 were the most expressed genes, while CCL4 and EGF were the less expressed genes. After neurotensin exposure, IL-8 mRNA expression was increased while CCL11 was decreased, suggesting a proinflammatory upregulation and chemoattractant ability downregulation of fibroblasts. Under inflammatory conditions, gene expression was significantly increased. After neurotensin exposure, CCL4 and IL-6 mRNA expression were decreased while CCL11 was increased, suggesting again a decrease in the chemoattractant capacity of fibroblasts and in their proinflammatory status. Furthermore, the expression of EGF, a crucial growth factor for skin cells proliferation and WH, was increased in all conditions. Overall, neurotensin, released by nerve fibers or skin cells, may be involved in the decrease of the chemotaxis and the proinflammatory status in the proliferation and remodelling phases of WH. Lucília Pereira da Silva, Bruno Miguel Neves, Liane Moura, Maria Teresa Cruz, and Eugénia Carvalho Copyright © 2014 Lucília Pereira da Silva et al. All rights reserved. Systemic Inflammatory Response during Laparotomy Tue, 05 Aug 2014 07:37:14 +0000 Background. The aim of this study was to analyze the influence of laparotomy on the systemic inflammatory response in human patients suffering from secondary peritonitis. Study Design. A prospective study investigating the levels of white blood cells, C-reactive protein, platelets, interleukin-six, and tumor necrosis factor-alpha during laparotomy in five patients who suffered from secondary peritonitis. Six venous blood samples were collected perioperatively from each patient. The data were summarized by descriptive statistics and presented in a box plot. The hypothesis was that laparotomy increases the systemic inflammatory response, as has been described in animal models in previous studies. Results. The median age of the patients in this study was 84 years, the male to female ratio was 2 : 3, and the mortality rate was 80%. The most common cause of generalized peritonitis was ischemia of the colon. Analysis of the data showed no significant changes in the level of plasma inflammatory mediators during the surgical procedure, except for the platelet count which showed a significant decrease . Conclusions. In contrast to experience with animal models, laparotomy in human patients with secondary peritonitis did not significantly increase the systemic inflammatory response. Furthermore, it contributed in significantly decreasing some of the systemic inflammatory mediators. Ahmad Mahamid, Basel Jabarin, and Gidon Almogy Copyright © 2014 Ahmad Mahamid et al. All rights reserved. Th17 Cells in Autoimmune and Infectious Diseases Sun, 03 Aug 2014 12:29:32 +0000 The view of CD4 T-cell-mediated immunity as a balance between distinct lineages of Th1 and Th2 cells has changed dramatically. Identification of the IL-17 family of cytokines and of the fact that IL-23 mediates the expansion of IL-17-producing T cells uncovered a new subset of Th cells designated Th17 cells, which have emerged as a third independent T-cell subset that may play an essential role in protection against certain extracellular pathogens. Moreover, Th17 cells have been extensively analyzed because of their strong association with inflammatory disorders and autoimmune diseases. Also, they appear to be critical for controlling these disorders. Similar to Th1 and Th2 cells, Th17 cells require specific cytokines and transcription factors for their differentiation. Th17 cells have been characterized as one of the major pathogenic Th cell populations underlying the development of many autoimmune diseases, and they are enhanced and stabilized by IL-23. The characteristics of Th17 cells, cytokines, and their sources, as well as their role in infectious and autoimmune diseases, are discussed in this review. José Francisco Zambrano-Zaragoza, Enrique Jhonatan Romo-Martínez, Ma. de Jesús Durán-Avelar, Noemí García-Magallanes, and Norberto Vibanco-Pérez Copyright © 2014 José Francisco Zambrano-Zaragoza et al. All rights reserved. Involvement of NF-κB/IL-6 Pathway in the Processing of Colorectal Carcinogenesis in Colitis Mice Sun, 29 Jun 2014 08:54:42 +0000 Nuclear factor-kappaB (NF-κB)/interleukin (IL-6) pathway links chronic inflammation to colitis associated cancer (CAC). In this study, we examined the dynamic temporal changes of the NF-κB/IL-6 pathway during the procession of experimental CAC mouse model. Mice were sacrificed after induction for 14, 16, 18, and 22 weeks for the examination of tumor burden, inflammation degree, and protein level of NF-κB and IL-6 in bowel tissues. The results showed that tumor burden and inflammation severity in the bowels were gradually increased over the observed time-points. The expressions of IL-6 and NF-κB proteins were gradually increased after induction of dysplastic lesions over times. These data provide new information on the dynamic temporal changes of NF-κB/IL-6 pathway in relation to CAC development that may be relevant in the design of future investigations of therapeutic interventions to effectively target CAC processes. Hang Yang, Haili Qi, Jingli Ren, Jing Cui, Zhenfeng Li, Helge L. Waldum, and Guanglin Cui Copyright © 2014 Hang Yang et al. All rights reserved. Limited Applicability of GW9662 to Elucidate PPARγ-Mediated Fatty Acid Effects in Primary Human T-Helper Cells Wed, 25 Jun 2014 05:42:25 +0000 Synthetic antagonists of the nuclear receptor PPARγ such as GW9662 are widely used to elucidate receptor-mediated ligand effects. In addition and complementary to recent work, we examined whether GW9662 is suitable to serve for mechanistic investigation in T-helper cells. Human peripheral blood mononuclear cells (PBMC) were preincubated with increasing concentrations of GW9662 (0, 0.4, 2, and 10 μmol/L) 30 min before adding the c9,t11-isomer of conjugated linoleic acid (c9,t11-CLA) as representative of PPARγ-activating fatty acids with immunomodulatory properties. Corresponding cultures were incubated with GW9662 in the absence of the fatty acid. After 19 h, cells were mitogen stimulated for further 5 h. Subsequently, intracellular IL-2 was measured in CD3+CD4+ lymphocytes by means of flow cytometry. 100 μmol/L c9,t11-CLA reduced the number of T-helper cells expressing IL-2 by 68%. GW9662 failed to abrogate this fatty acid effect, likely due to the fact that the compound exerted an own inhibitory effect on IL-2 production. Moreover, GW9662 dose-dependently induced cell death in human leukocytes. These results suggest that application of GW9662 is not conducive in this experimental setting. Anke Jaudszus, Stefan Lorkowski, Michael Gruen, Alexander Roth, and Gerhard Jahreis Copyright © 2014 Anke Jaudszus et al. All rights reserved. 5-Aminosalicylic Acid Inhibits Acute Clostridium difficile Toxin A-Induced Colitis in Rats Mon, 23 Jun 2014 00:00:00 +0000 We tested the hypothesis that 5-aminosalicylic acid (5-ASA) inhibits toxin A-induced generation of colonic leukotriene B4 (LTB4) and toxin A colitis in rats. Isolated colonic segments in anesthetized rats were treated intraluminally with toxin A for 3 hours with or without 30 minutes of pretreatment with either 5-ASA or sulfapyridine and then colonic tissue levels of LTB4 were measured and inflammation was assessed. Separately, sulfasalazine was administered to rats in their drinking water for 5 days, isolated colonic segments were then prepared, toxin A was administered, and inflammation was assessed as before. Pretreatment with 5-ASA inhibited toxin A-induced increased tissue LTB4 concentration in the colon. Sulfasalazine and 5-ASA but not sulfapyridine significantly inhibited toxin A colitis. However, pretreatment with 5-ASA did not protect against direct TRPV1-mediated colitis caused by capsaicin. Toxin A stimulated the release of substance P (SP), and this effect was also inhibited by sulfasalazine and 5-ASA but not by sulfapyridine. Thus, toxin A stimulates colonic LTB4 resulting in activation of TRPV1, release of SP, and colitis. Inhibition of 5-LO by 5-ASA disrupts this pathway and supports the concept that LTB4 activation of TRPV1 plays a role in toxin A colitis. Steven R. Vigna Copyright © 2014 Steven R. Vigna. All rights reserved. Prophylactic Antioxidant Potential of Gallic Acid in Murine Model of Sepsis Wed, 11 Jun 2014 11:31:50 +0000 Present study is to investigate the effect of Gallic acid pretreatment on survival of septic animals and oxidative stress in different organs like lungs, liver, kidney, spleen, and vascular dysfunction of mice. Sepsis was induced by cecal ligation and puncture (CLP) in healthy adult male albino mice (25–30 g) and was divided into 3 groups each consisting of 6 animals, that is, sham-operated (SO group (Group I), SO + sepsis (Group II), and Gallic acid + sepsis (Group III)). Group III animals were pretreated with Gallic acid at the dose rate of 20 mg/kg body weight for 2 days before induction of sepsis. Animals were sacrificed on 8th day and the tissue samples were obtained for further investigation on lipid peroxidation (LPO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSH). Gallic acid pretreatment significant () reduces kidney, spleen, liver, and lungs’ malondialdehyde level in septic mice. However, it fails to improve reduced glutathione level in all given organs, while, Gallic acid pretreated mice showed significant improvement in SOD activity of kidney and spleen when compared to septic mice. Finally, the beneficial effects of Gallic acid pretreatment in sepsis are evident from the observations that Gallic acid partially restored SOD and catalase activity and completely reversed lipid peroxidation. Further studies are required to find out the possible mechanisms underlying the beneficial effects of Gallic acid on large population. Harikesh Maurya, Vaishali Mangal, Sanjay Gandhi, Kathiresan Prabhu, and Kathiresan Ponnudurai Copyright © 2014 Harikesh Maurya et al. All rights reserved. The Role of Intracellular Organisms in the Pathogenesis of Inflammatory Arthritis Thu, 05 Jun 2014 06:27:58 +0000 Inflammatory arthritis is a condition which is characterised by recurrent episodes of joint pain and swelling. It encompasses a spectrum of disorders ranging from rheumatoid arthritis to ankylosing spondylitis. In these conditions, for reasons that are poorly understood, the immune system raises an inflammatory response within the joint space. In some cases, autoantigens have been identified (e.g., anticitrullinated peptides in rheumatoid arthritis), but the absence of these, in the seronegative arthritides, for example, raises question as to the underlying pathogenesis. Interest has, therefore, turned to host-pathogen interactions and whether aberrant immune responses to these could explain the development of arthritis. This has been most widely studied in reactive arthritis (ReA), where an infectious episode precedes the development of the joint symptoms. In this review, we present the evidence for the role of host-bacterial interactions in the pathogenesis of joint inflammation with particular emphasis on ReA. We discuss a range of possible mechanisms including molecular mimicry, persistent low grade infections, and abnormal host responses to common bacterial causes of reactive arthritis as well as discussing some of the clinical challenges that we face in making the diagnosis and in treatment of persistent symptoms. Animesh Singh and Sarah Karrar Copyright © 2014 Animesh Singh and Sarah Karrar. All rights reserved. Wogonin Attenuates Ovalbumin Antigen-Induced Neutrophilic Airway Inflammation by Inhibiting Th17 Differentiation Wed, 28 May 2014 13:13:55 +0000 Allergic airway inflammation is generally considered to be a Th2-type immune response. Recent studies, however, have demonstrated that Th17-type immune responses also play important roles in this process, particularly in the pathogenesis of neutrophilic airway inflammation, a hallmark of severe asthma. We scrutinized several Kampo extracts that reportedly exhibit anti-inflammatory activity by using in vitro differentiation system of human and mouse naïve T cells. We found that hange-shashin-to (HST) and oren-gedoku-to (OGT) possess inhibitory activity for Th17 responses in vitro. Indeed, wogonin and berberine, major components common to HST and OGT, exhibit Th17-inhibitory activities in both murine and human systems in vitro. We therefore evaluated whether wogonin suppresses OVA-induced neutrophilic airway inflammation in OVA TCR-transgenic DO11.10 mice. Consequently, oral administration of wogonin significantly improved OVA-induced neutrophilic airway inflammation. Wogonin suppressed the differentiation of naïve T cells to Th17 cells, while showing no effects on activated Th17 cells. Rie Takagi, Masaaki Kawano, Kazuyuki Nakagome, Kumiko Hashimoto, Takehiro Higashi, Katsuya Ohbuchi, Atsushi Kaneko, and Sho Matsushita Copyright © 2014 Rie Takagi et al. All rights reserved. Posttranscriptional Suppression of Lipopolysaccharide-Stimulated Inflammatory Responses by Macrophages in Middle-Aged Mice: A Possible Role for Eukaryotic Initiation Factor 2α Mon, 07 Apr 2014 13:38:44 +0000 The intensities of macrophage inflammatory responses to bacterial components gradually decrease with age. Given that a reduced rate of protein synthesis is a common age-related biochemical change, which is partially mediated by increased phosphorylation of eukaryotic initiation factor-2α (eIF-2α), we investigated the mechanism responsible for the deterioration of macrophage inflammatory responses, focusing specifically on the age-related biochemical changes in middle-aged mice. Peritoneal macrophages isolated from 2-month-old (young) and 12-month-old (middle-aged) male BALB/c mice were stimulated with lipopolysaccharide (LPS). Although LPS-stimulated secretion of tumor necrosis factor-α (TNF-α) by the macrophages from middle-aged mice was significantly lower than that from young mice, LPS caused marked increases in levels of TNF-α mRNA in macrophages from middle-aged as well as young mice. Moreover, LPS evoked similar levels of phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) in young and middle-aged mice. In contrast, the basal level of phosphorylated eIF-2α in macrophages from middle-aged mice was higher than that in macrophages from young mice. Salubrinal, an inhibitor of the phosphatase activity that dephosphorylates eIF-2α, suppressed the LPS-stimulated inflammatory responses in a murine macrophage cell line RAW264.7. These results suggest that posttranscriptional suppression of macrophage inflammatory responses during middle age requires phosphorylation of eIF-2α. Ken Shirato and Kazuhiko Imaizumi Copyright © 2014 Ken Shirato and Kazuhiko Imaizumi. All rights reserved. The Renin-Angiotensin-Aldosterone System in Vascular Inflammation and Remodeling Sun, 06 Apr 2014 06:43:49 +0000 The RAAS through its physiological effectors plays a key role in promoting and maintaining inflammation. Inflammation is an important mechanism in the development and progression of CVD such as hypertension and atherosclerosis. In addition to its main role in regulating blood pressure and its role in hypertension, RAAS has proinflammatory and profibrotic effects at cellular and molecular levels. Blocking RAAS provides beneficial effects for the treatment of cardiovascular and renal diseases. Evidence shows that inhibition of RAAS positively influences vascular remodeling thus improving CVD outcomes. The beneficial vascular effects of RAAS inhibition are likely due to decreasing vascular inflammation, oxidative stress, endothelial dysfunction, and positive effects on regeneration of endothelial progenitor cells. Inflammatory factors such as ICAM-1, VCAM-1, TNF, IL-6, and CRP have key roles in mediating vascular inflammation and blocking RAAS negatively modulates the levels of these inflammatory molecules. Some of these inflammatory markers are clinically associated with CVD events. More studies are required to establish long-term effects of RAAS inhibition on vascular inflammation, vascular cells regeneration, and CVD clinical outcomes. This review presents important information on RAAS’s role on vascular inflammation, vascular cells responses to RAAS, and inhibition of RAAS signaling in the context of vascular inflammation, vascular remodeling, and vascular inflammation-associated CVD. Nevertheless, the review also equates the need to rethink and rediscover new RAAS inhibitors. Maricica Pacurari, Ramzi Kafoury, Paul B. Tchounwou, and Kenneth Ndebele Copyright © 2014 Maricica Pacurari et al. All rights reserved. Interleukin-17A Exacerbates Ferric Chloride-Induced Arterial Thrombosis in Rat Carotid Artery Thu, 03 Apr 2014 15:49:45 +0000 Interleukin-17A (IL-17A), the most widely studied member of the IL-17 cytokine family, is a cytokine which emerged to be critical for host defense as well as in the pathogenesis of autoimmune disorders. Moreover, IL-17A is involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis and acute coronary syndrome and in the cardiovascular risk associated with systemic immunological disorders. Consistent with this, we have recently shown that IL-17A increases human and murine platelet response to ADP. In this study we expanded our previous observation and we describe for the first time an in vivo prothrombotic effect of the cytokine. Our results show that IL-17A is synergic with a low FeCl3 concentration in inducing carotid thrombus in rats and suggest that the effect is likely related to a downregulation of CD39 vascular expression and hydrolyzing activity. Our findings indicate that IL-17A might be an important molecule at the interface between hemostasis and inflammation. Francesco Maione, Antonio Parisi, Elisabetta Caiazzo, Silvana Morello, Fulvio D'Acquisto, Nicola Mascolo, and Carla Cicala Copyright © 2014 Francesco Maione et al. All rights reserved. Differential Role of Rapamycin and Torin/KU63794 in Inflammatory Response of 264.7 RAW Macrophages Stimulated by CA-MRSA Tue, 01 Apr 2014 11:55:30 +0000 Background. Rapamycin suppresses the RAW264.7 macrophage mediated inflammatory response but in lower doses induces it. In the present study, we tested the suppression of the inflammatory response in the presence of mTOR 1 and 2 inhibitors, Torin and KU63794. Methods. RAW264.7 cells were stimulated for 18 hrs with 106 to 107 CFU/mL inocula of community-acquired- (CA-) MRSA isolate, USA400 strain MW2, in the presence of Vancomycin. Then, in sequential experiments, we added Torin, KU63794, and Rapamycin alone and in various combinations. Supernatants were collected and assayed for TNF, IL-1, IL-6, INF, and NO. Results. Rapamycin induces 10–20% of the inflammatory cascade at dose of 0.1 ng/mL and suppresses it by 60% at dose of 10 ng/mL. The induction is abolished in the presence of Torin KU63794. Torin and KU63794 are consistently suppressing cytokine production 50–60%. Conclusions. There is a differential response between Rapamycin (mTOR-1 inhibitor) and Torin KU63794 (mTOR 1 and 2 inhibitors). Torin and KU63794 exhibit a dose related suppression. Rapamycin exhibits a significant induction-suppression biphasic response. Knowledge of such response may allow manipulation of the septic inflammatory cascade for clinical advantages. Rebekah K. H. Shappley and Thomas Spentzas Copyright © 2014 Rebekah K. H. Shappley and Thomas Spentzas. All rights reserved. The Serum S100B Level as a Biomarker of Enteroglial Activation in Patients with Ulcerative Colitis Sun, 30 Mar 2014 12:08:08 +0000 Objective. Recent studies have demonstrated that enteric glial cells (EGC) participate in the homeostasis of the gastrointestinal tract. This study investigated whether enteroglial markers, including S100B protein and glial fibrillary acidic protein (GFAP), can serve as noninvasive indicators of EGC activation and disease activity in UC patients. Methods. This clinical prospective study included 35 patients with UC and 40 age- and sex-matched controls. The diagnosis of UC was based on standard clinical, radiological, endoscopic, and histological criteria. Clinical disease activity was evaluated using the Modified Truelove-Witts Severity Index. Serum samples were analyzed for human GFAP and S100B using commercial enzyme-linked immunosorbent assay kits. Results. GFAP was not detected in the serum of either UC patients or controls (). However, we found a significant () decrease in the serum S100B levels in the UC patients. No correlation between the serum S100B level and the disease activity or duration was observed (). The serum S100B levels did not differ between UC patients with active disease (24 patients, 68.6%) or in remission (11 patients, 31.4%) (). Conclusions. Ulcerative colitis patients had significantly lower serum S100B levels, while GFAP was of no diagnostic value in UC patients. Asuman Celikbilek, Mehmet Celikbilek, Seda Sabah, Nermin Tanık, Elif Borekci, Serkan Dogan, Yavuz Akin, Suleyman Baldane, Kemal Deniz, Neziha Yilmaz, Omer Ozbakir, and Mehmet Yucesoy Copyright © 2014 Asuman Celikbilek et al. All rights reserved. Carbon Black Particle Exhibits Size Dependent Toxicity in Human Monocytes Wed, 05 Feb 2014 11:44:24 +0000 Increased levels of particulate air pollution are associated with increased respiratory and cardiovascular mortality and morbidity. Some epidemiologic and toxicological researches suggest ultrafine particles (<100 nm) to be more harmful per unit mass than larger particles. In the present study, the effect of particle size (nano and micro) of carbon black (CB) particle on viability, phagocytosis, cytokine induction, and DNA damage in human monocytes, THP-1 cells, was analysed. The cells were incubated with nanosize (~50 nm) and micron (~500 nm) size of CB particles in a concentration range of 50–800 µg/mL. The parameters like MTT assay, phagocytosis assay, ELISA, gene expression, and DNA analysis were studied. Exposure to nano- and micron-sized CB particles showed size- and concentration dependent decrease in cell viability and significant increase in proinflammatory cytokines IL-1β, TNF-α and IL-6 as well as chemokine IL-8 release. Gene expression study showed upregulation of monocyte chemoattractant protein-1 gene while cyclooxygenase-2 gene remained unaffected. Nano CB particles altered the phagocytic capacity of monocytes although micron CB had no significant effect. CB particles did not show any significant effect on DNA of monocytes. The investigations indicate that CB particles in nanosize exhibit higher propensity of inducing cytotoxicity, inflammation, and altered phagocytosis in human monocytes than their micron size. Devashri Sahu, G. M. Kannan, and R. Vijayaraghavan Copyright © 2014 Devashri Sahu et al. All rights reserved. Clinical Feature of Intrahepatic B-Lymphocytes in Chronic Hepatitis B Tue, 21 Jan 2014 14:24:30 +0000 Humoral immunity constitutes major defense mechanism against viral infections. However, the association of hepatic injury and B-cells population in chronic hepatitis B virus (HBV) carriers has not been studied well. In this study, fifty seven hepatitis B surface antigen (HBsAg) positive and HBeAg negative patients were studied to determine the expression of CD20, a cell surface marker expressed on B-cells, in liver biopsy sections using immunohistochemistry. The patients’ clinical data at the time of liver biopsy were acquired from their medical records. There was a significant association between log HBV DNA and both ALT (, ) and histologic activity index (HAI) total score (, ), respectively. The CD20 was expressed in all 57 liver biopsy samples with a submembranous and membranous staining pattern and its expression was significantly associated with HAI total score (, ) and stage of fibrosis (, ). The susceptible B lymphocytes to hepatitis B virus might be implicated in the development of immune mediated inflammation of HBV-induced hepatic injury. The present data also support that the liver is potentially one of the secondary lymphoid organs. Ashraf Mohamadkhani, Elnaz Naderi, Masoud Sotoudeh, Aezam Katoonizadeh, Ghodratollah Montazeri, and Hossein Poustchi Copyright © 2014 Ashraf Mohamadkhani et al. All rights reserved. Parecoxib Reduces Systemic Inflammation and Acute Lung Injury in Burned Animals with Delayed Fluid Resuscitation Tue, 21 Jan 2014 10:03:08 +0000 Burn injuries result in the release of proinflammatory mediators causing both local and systemic inflammation. Multiple organ dysfunctions secondary to systemic inflammation after severe burn contribute to adverse outcome, with the lungs being the first organ to fail. In this study, we evaluate the anti-inflammatory effects of Parecoxib, a parenteral COX-2 inhibitor, in a delayed fluid resuscitation burned rat model. Anaesthetized Sprague Dawley rats were inflicted with 45% total body surface area full-thickness scald burns and subsequently subjected to delayed resuscitation with Hartmann’s solution. Parecoxib (0.1, 1.0, and 10 mg/kg) was delivered intramuscularly 20 min after injury followed by 12 h interval and the rats were sacrificed at 6 h, 24 h, and 48 h. Burn rats developed elevated blood cytokines, transaminase, creatinine, and increased lung MPO levels. Animals treated with 1 mg/kg Parecoxib showed significantly reduced plasma level of CINC-1, IL-6, PGEM, and lung MPO. Treatment of 1 mg/kg Parecoxib is shown to mitigate systemic and lung inflammation without significantly affecting other organs. At present, no specific therapeutic agent is available to attenuate the systemic inflammatory response secondary to burn injury. The results suggest that Parecoxib may have the potential to be used both as an analgesic and ameliorate the effects of lung injury following burn. Si Jack Chong, Yong Chiat Wong, Jian Wu, Mui Hong Tan, Jia Lu, and Shabbir M. Moochhala Copyright © 2014 Si Jack Chong et al. All rights reserved. Necrotizing Soft Tissue Infections: Surgeon’s Prospective Tue, 24 Dec 2013 18:20:53 +0000 Necrotizing soft tissue infections (NSTIs) are fulminant infections of any layer of the soft tissue compartment associated with widespread necrosis and systemic toxicity. Delay in diagnosing and treating these infections increases the risk of mortality. Early and aggressive surgical debridement with support for the failing organs significantly improves the survival. Although there are different forms of NSTIs like Fournier’s gangrene or clostridial myonecrosis, the most important fact is that they share common pathophysiology and principles of treatment. The current paper summarizes the pathophysiology, clinical features, the diagnostic workup required and the treatment principles to manage these cases. Shashi Prakash Mishra, Shivanshu Singh, and Sanjeev Kumar Gupta Copyright © 2013 Shashi Prakash Mishra et al. All rights reserved. Risk Factors for Chronic Mastitis in Morocco and Egypt Thu, 14 Nov 2013 09:38:52 +0000 Chronic mastitis is a prolonged inflammatory breast disease, and little is known about its etiology. We identified 85 cases and 112 controls from 5 hospitals in Morocco and Egypt. Cases were women with chronic mastitis (including periductal, lobular, granulomatous, lymphocytic, and duct ectasia with mastitis). Controls had benign breast disease, including fibroadenoma, benign phyllodes, and adenosis. Both groups were identified from histopathologically diagnosed patients from 2008 to 2011, frequency-matched on age. Patient interviews elicited demographic, reproductive, breastfeeding, and clinical histories. Cases had higher parity than controls (OR = 1.75, 1.62–1.90) and more reported history of contraception use (OR = 2.73, 2.07–3.61). Cases were less likely to report wearing a bra (OR = 0.56, 0.47–0.67) and less often used both breasts for breastfeeding (OR = 4.40, 3.39–5.72). Chronic mastitis cases were significantly less likely to be employed outside home (OR = 0.71, 0.60–0.84) and more likely to report mice in their households (OR = 1.63, 1.36–1.97). This is the largest case-control study reported to date on risk factors for chronic mastitis. Our study highlights distinct reproductive risk factors for the disease. Future studies should further explore these factors and the possible immunological and susceptibility predisposing conditions. Hanna N. Oltean, Amr S. Soliman, Omar S. Omar, Tamer F. Youssef, Mehdi Karkouri, Azza Abdel-Aziz, Ahmad Hablas, Taylor Blachley, Ali Tahri, and Sofia D. Merajver Copyright © 2013 Hanna N. Oltean et al. All rights reserved.