Home About us Contact
|
Home About us Contact | ||
|
|
||
Inflammatory Mediators (inflammatory + mediator)
Kinds of Inflammatory Mediators Selected AbstractsCYTOKINES AND INFLAMMATORY MEDIATORSINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 2006Article first published online: 6 JUL 200 First page of article [source] AQP1 and AQP3, Psoriasin, and Nitric Oxide Synthases 1,3 are Inflammatory Mediators in Erythema Toxicum NeonatorumPEDIATRIC DERMATOLOGY, Issue 5 2003Giovanna Marchini M.D., Ph.D. Its etiology and physiologic significance are still unclear. The purpose of this study was to extend the search for possible inflammatory mediators of the rash. We performed immunohistochemistry on punch biopsy cryosections from lesions of four, 1-day-old infants and from four matched controls without rash, using antibodies against the water channel proteins aquaporin-1 (AQP1) and aquaporin-3 (AQP3), psoriasin, and the nitric oxide synthase (NOS) enzymes, neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). All sections from the lesions showed a dense, nodular cellular infiltrate located near the hair follicle. The vessels in the dermis showed a high incidence of AQP1 and eNOS. Strong staining for AQP1, AQP3, and psoriasin, as well as nNOS, iNOS, and eNOS were seen in the entire epidermal layer. The infiltrate in the dermis contained numerous cells expressing AQP1, AQP3, nNOS, iNOS, and eNOS. Double immunofluorescence staining showed that AQP3 was located in CD1a-expressing Langerhans cells and other dendritic cells in the dermis, as well as in CD14-expressing macrophages, CD15-expressing neutrophils, and EG2-expressing eosinophils surrounding the hair follicle. Our findings show that AQP1 and AQP3, psoriasin, and NOSs are involved in the activation of the skin immune system at birth. [source] Inflammation and drug hepatotoxicity: Aggravation of injury or clean-up mission?,HEPATOLOGY, Issue 5 2005Hartmut Jaeschke BACKGROUND & AIMS Inflammatory mediators released by nonparenchymal inflammatory cells in the liver have been implicated in the progression of acetaminophen (APAP) hepatotoxicity. Among hepatic nonparenchymal inflammatory cells, we examined the role of the abundant natural killer (NK) cells and NK cells with T-cell receptors (NKT cells) in APAP-induced liver injury. METHODS C57BL/6 mice were administered a toxic dose of APAP intraperitoneally to cause liver injury with or without depletion of NK and NKT cells by anti-NK1.1 monoclonal antibody (MAb). Serum alanine transaminase (ALT) levels, liver histology, hepatic leukocyte accumulation, and cytokine/chemokine expression were assessed. RESULTS Compared with APAP-treated control mice, depletion of both NK and NKT cells by anti-NK1.1 significantly protected mice from APAP-induced liver injury, as evidenced by decreased serum ALT level, improved survival of mice, decreased hepatic necrosis, inhibition of messenger RNA (mRNA) expression for interferon-gamma (IFN-gamma), Fas ligand (FasL), and chemokines including KC (Keratinocyte-derived chemokine); MIP-1 alpha (macrophage inflammatory protein-1 alpha); MCP-1 (monocyte chemoattractant protein-1); IP-10 (interferon-inducible protein); Mig (monokine induced by IFN-gamma) and decreased neutrophil accumulation in the liver. Hepatic NK and NKT cells were identified as the major source of IFN-gamma by intracellular cytokine staining. APAP induced much less liver injury in Fas-deficient (lpr) and FasL-deficient (gld) mice compared with that in wild-type mice. CONCLUSIONS NK and NKT cells play a critical role in the progression of APAP-induced liver injury by secreting IFN-gamma, modulating chemokine production and accumulation of neutrophils, and up-regulating FasL expression in the liver, all of which may promote the inflammatory response of liver innate immune system, thus contributing to the severity and progression of liver injury downstream of the metabolism of APAP and depletion of reduced glutathione (GSH) in hepatocytes. [source] Childhood asthma: Exhaled markers of airway inflammation, asthma control score, and lung function testsPEDIATRIC PULMONOLOGY, Issue 2 2004Philippe P.R. Rosias MD Abstract Exhaled markers of airway inflammation become increasingly important in the management of childhood asthma. The aims of the present study are: 1) to compare exhaled markers of inflammation (nitric oxide, carbon monoxide, and acidity of breath condensate) with conventional asthma measures (lung function tests and asthma control score) in childhood asthma; and 2) to investigate the detectability of albumin, CRP, IL-6, IL-8, TNF-alpha, sICAM-1, and sTNF-R75 in the exhaled breath condensate (EBC) of asthmatic children. Thirty-two children with mild to moderate persistent asthma and healthy controls aged 6,12 years were studied. We measured exhaled NO and CO, and subsequently EBC was collected. Inflammatory mediators in EBC were measured using an enzyme-linked immunosorbent assay. Respiratory symptoms and asthma control were assessed using the asthma control questionnaire (ACQ) of Juniper et al. (Eur Respir J 1999;14:902,907). Exhaled NO showed a significant correlation with exhaled CO (r,=,0.59, P,<,0.05) and FEV1 (r,=,,0.59, P,<,0.05), but not with ACQ score (r,=,0.48, P,=,0.06). Exhaled CO was correlated with prebronchodilator FEV1 (r,=,,0.45, P,<,0.05), but not with asthma control (r,=,0.18, P,=,0.35). Acidity of EBC was significantly lower in asthmatic children than in healthy controls (P,<,0.05), but did not correlate with any of the conventional asthma measures. We were not able to demonstrate the presence of CRP, IL-6, IL-8, TNF-alpha, sICAM-1, and sTNF-R75 in EBC. Albumin was found in two EBC samples of asthmatic children. We conclude that exhaled NO had a better correlation with lung function parameters and asthma control than exhaled CO and acidity of EBC, in mild to moderate persistent childhood asthma. However, exhaled NO, CO, and deaerated pH of EBC did not differ between asthmatic children and controls, possibly because of a too homogeneous and well-controlled study population. To further evaluate the clinical utility of exhaled markers in monitoring childhood asthma, more studies are required on a wider range of asthma severity, and preferably with repeated measurements of markers and of asthma control. Pediatr Pulmonol. 2004; 38:107,114. © 2004 Wiley-Liss, Inc. [source] Effect of Inhibitor of Tumor Necrosis Factor-, and Oxatomide on Immune Mediated Otitis MediaTHE LARYNGOSCOPE, Issue 9 2006Yong-Soo Park MD Abstract Objective: Inflammatory mediators (IMs) play a major role in the production of middle ear effusion (MEE). Tumor necrosis factor (TNF)-, and leukotrienes (LTs) appear to be important in the pathogenesis of otitis media with effusion (OME). The purpose of this study is to determine the effect of TNF-, and LT antagonist on the outcome of experimental immune-mediated OME. Study Design: Prospective. Methods: Otitis media was induced in rats by injecting keyhole limpet hemocyanin (KLH) transtympanically 7 days after systemic immunization. Experimental groups were treated with soluble TNF receptor type I (sTNF RI) or oxatomide simultaneously. Seventy-two hours after transtympanic injection, MEE was aspirated, and temporal bone was taken. Vascular permeability (VP) of the middle ear mucosa was measured using the Evans blue dye technique. Hematoxylin-eosin stain and immunohistochemical stain for leukocyte common antigen was performed. Results: In KLH, sTNF RI, and oxatomide groups, MEE was developed in 83%, 0%, and 66% of the ears, respectively. The sTNF RI group showed significant decrease in effusion production, inflammation, mucosal thickening, and VP compared with the KLH group. These parameters were less significant in the oxatomide group than in the sTNF RI group. Conclusion: Transtympanic administration of sTNF RI and oxatomide appears to suppress the development of immune-mediated MEE. [source] Medullary pain facilitating neurons mediate allodynia in headache-related pain,ANNALS OF NEUROLOGY, Issue 2 2009Rebecca M. Edelmayer BS Objective To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. Methods Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized. Results IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene,related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM. Interpretation Facial and hind-paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders. Ann Neurol 2009;65:184,193 [source] 4156: Inflammatory mediators in the aqueous humor from patients with uveitis associated with Behçet's disease and Vogt-Koyanagi-Harada diseaseACTA OPHTHALMOLOGICA, Issue 2010A ABU EL ASRAR Purpose We studied interphotoreceptor retinoid-binding protein (IRBP), a dominant autoimmune antigen in the eye. Methods Aqueous humour samples from 28 patients with active uveitis were analysed for immunoglobulin G (IgG) content as a marker for blood-ocular barrier breakdown and by gelatinase B zymography for the detection of inflammation. The data were correlated with the presence of intact IRBP (approximately 140 kD) as determined by Western blot analysis and with the clinical disease activity. Results Aqueous humour samples from control eyes and eyes with low disease activity showed positive immunoreactivity for intact IRBP. The IRBP signal weakened or disappeared with higher disease activity. Significant positive correlations were observed between disease activity and levels of gelatinase B/matrix metalloproteinase-9 (MMP-9) (rs=0.713; P<0.001) and IgG (rs=0.580; P=0.001). Significant negative correlations were found between levels of IRBP and disease activity (rs=-0.520; P=0.005) and levels of MMP-9 (rs=-0.727; P<0.001) and of IgG (rs=-0.834; P<0.001). Whereas neutrophil elastase converted intact IRBP into an immunoreactive 55 kD peptide in vitro, the conversion by neutrophil degranulates resembled more the in vivo context with a complete degradation of IRBP. Reversal of inflammation with immunosuppressive therapy was accompanied with reappearance of intact IRBP and disappearance of IgG and MMP-9. Conclusion The analysis of IRBP proteolysis is useful as a biomarker for uveitis and suggests that inhibition of proteinases might become a therapeutic strategy in an inflammatory context of a damaged blood-ocular barrier. [source] Inflammatory mediators in perinatal asphyxia and infectionACTA PAEDIATRICA, Issue 2002M Xanthou Aim: To determine serum levels of interleukin-6 (IL-6), IL-1,, tumor necrosis factor-, (TNF-,), soluble intercellular adhesion molecule-1 (sICAM-1) and C-reactive protein (CRP) in asphyxiated neonates and compare these inflammatory factors with those found in neonates with perinatal infection. Methods: 88 neonates were studied, of whom 36 were asphyxiated, 18 were infected and the remaining 34 were controls. Peripheral blood samples were obtained on the 1st, 3rd and 5th postnatal days. Results: Cytokines IL-6 and IL-1, as well as sICAM-1 serum levels did not differ between asphyxiated and infected neonates; however, at most time periods, their values were significantly higher than controls. TNF-, was similar in the three groups of neonates. CRP serum values were significantly higher in the infected neonates than in the asphyxiated or control subjects. Among the 54 asphyxiated and infected neonates, 15 were considered as severe cases and 39 as mild. The severe cases, at most time periods, had significantly higher IL-6, IL-1, and sICAM-1 levels compared with the mild ones. Through receiver operating characteristic curves the cut-off points, sensitivities, and specificities for distinguishing neonates at risk or at high risk for brain damage were established. Conclusion: Similar increases in serum levels of IL-6, IL-1, and sICAM-1 were found in perinatally asphyxiated and infected neonates. As these increases correlated with the severity of the perinatal insults, neonates at high risk for brain damage might be detected. [source] Nitric oxide synthase type-II is synthesized by human gingival tissue and cultured human gingival fibroblastsJOURNAL OF PERIODONTAL RESEARCH, Issue 4 2000H. K. Kendall Nitric oxide is known to be an important inflammatory mediator, and is implicated in the pathophysiology of a range of inflammatory disorders. The aim of this study was to determine the localization and distribution of endothelial NOS (NOSII) in human gingival tissue, and to ascertain if human gingival fibroblasts express NOS-II when stimulated with interferon gamma (IFN-,) and bacterial lipopolysaccharide (LPS). The distribution of NOS-II in inflamed and non-inflamed specimens of human gingivae was studied using a monoclonal antibody against nitric oxide synthase II. Cultures of fibroblasts derived from healthy human gingivae were used for the cell culture experiments. The results from immunohistochemical staining of the tissues indicated an upregulation of NOS-II expression in inflamed compared to non-inflamed gingival tissue. Fibroblasts and inflammatory cells within the inflamed connective tissue were positively stained for NOS-II. In addition, basal keratinocytes also stained strongly for NOS-II, in both healthy and inflamed tissue sections. When cultured human gingival fibroblasts were stimulated by INF-, and Porphyromonas gingivalis LPS, NOS-II was more strongly expressed than when the cells were exposed to LPS or IFN-, alone. These data suggest that, as for other inflammatory diseases, NO plays a role in the pathophysiology of periodontitis. [source] Mechanisms of cytoprotective effect of amino acids on local toxicity caused by sodium laurate, a drug absorption enhancer, in intestinal epitheliumJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2002Yoko Endo Abstract Several amino acids, including L -glutamine (L -Gln), were found to protect the intestinal epithelial cells from the local toxicity caused by a drug absorption enhancer, sodium laurate (C12), in our previous study. To develop more efficient and safer formulations for enhancing drug absorption, the mechanisms of cytoprotection by amino acids were studied using rats and Caco-2 cells. Four amino acids, including L -Gln, could generally maintain the absorption-promoting action of C12, although taurine tended to attenuate it. Three amino acids, except for L -Gln, significantly suppressed the decrease in the transepithelial electrical resistance caused by C12. Quercetin, an inhibitor for biosynthesis of heat shock protein 70 (HSP70), masked only the protective effect of L -Gln in both rat large intestine and Caco-2 cells. Western blot analysis indicated clearly that HSP70 is induced extensively only by the addition of L -Gln in both rat large-intestinal cells and Caco-2 cells. C12 was found to increase the intracellular concentration of Ca2+ ([Ca2+]i) remarkably, and amino acids, especially L -arginine, L -methionine, and taurine, significantly attenuated the increase in [Ca2+]i caused by C12. Furthermore, although C12 stimulated the release of histamine, an inflammatory mediator, from rat large-intestinal tissue, amino acids were also found to suppress the release of histamine enhanced by C12. The results in the present study showed that an induction of HSP70, a decrease in [Ca2+]i elevated by C12, and a suppression of histamine release stimulated by C12 should be involved in the mechanisms behind the cytoprotective action of amino acids against the local toxicity caused by C12. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:730,743, 2002 [source] Upregulation of Serotonin Transporter by Alcohol in Human Dendritic Cells: Possible Implication in Neuroimmune DeregulationALCOHOLISM, Issue 10 2009Dakshayani Kadiyala Babu Background:, Alcohol is the most widely abused substance and its chronic consumption causes neurobehavioral disorders. It has been shown that alcohol affects the function of immune cells. Dendritic cells (DC) serve as the first line of defense against infections and are known to accumulate neurotransmitters such as 5-hydroxytryptamine (5-HT). The enzyme monoamine oxidase-A (MAO-A) degrades 5-HT that is associated with clinical depression and other neurological disorders. 5-HT is selectively transported into neurons through the serotonin transporter (SERT), which is a member of the sodium- and chloride-dependent neurotransmitter transporter (SLC6) family. SERT also serves as a receptor for psychostimulant recreational drugs. It has been demonstrated that several drugs of abuse such as amphetamine and cocaine inhibit the SERT expression; however, the role of alcohol is yet to be elucidated. We hypothesize that alcohol can modulate SERT and MAO-A expression in DC, leading to reciprocal downregulation of 5-HT in extracellular medium. Methods:, Dendritic cells were treated with different concentrations (0.05% to 0.2%v/v) of alcohol for 24,72 hours and processed for SERT and MAO-A expression using Q-PCR and Western blots analysis. In addition, SERT function in DC treated with alcohol both in the presence and absence of imipramine, a SERT inhibitor was measured using 4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide uptake assay. 5-HT levels in culture supernatant and intracellular 5-hydroxy indole acetic acid (5-HIAA) and cyclic AMP were also quantitated using ELISA. Results:, Dendritic cells treated with 0.1% alcohol for 24 hours showed significant upregulation of SERT and MAO-A expression compared with untreated DC. We also observed that 0.1% alcohol enhanced the function of SERT and decreased extracellular 5-HT levels compared with untreated DC cultures, and this was associated with the elevation of intracellular 5-HIAA and cyclic AMP levels. Conclusions:, Our study suggests that alcohol upregulates SERT and MAO-A by elevating cyclic AMP, which may lead to decreased concentration of 5-HT in the extracellular medium. As 5-HT is a major neurotransmitter and an inflammatory mediator, its alcohol-mediated depletion may cause both neurological and immunological deregulation. [source] High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantationLIVER TRANSPLANTATION, Issue 10 2008Minna Ilmakunnas High mobility group box 1 protein (HMGB1), a cytokine actively secreted by phagocytes and passively released from necrotic cells, is an inflammatory mediator in experimental hepatic ischemia/reperfusion injury. We characterized its expression in human liver transplantation. In 20 patients, in addition to systemic samples, blood was drawn from portal and hepatic veins during and after reperfusion to assess changes within the graft. Plasma HMGB1, tumor necrosis factor , (TNF-,), and interleukin-6 (IL-6) levels were measured, and HMGB1 immunohistochemistry was performed on biopsies taken before and after reperfusion. Plasma HMGB1 was undetectable before reperfusion, and levels in systemic circulation peaked after graft reperfusion. At portal declamping, HMGB1 levels were substantially higher in the caval effluent [188 (80-371) ng/mL] than in portal venous blood [0 (0-3) ng/mL, P < 0.001]. HMGB1 release from the graft continued thereafter. HMGB1 levels were not related to TNF-, or IL-6 levels. HMGB1 expression was up-regulated in biopsies taken after reperfusion (P = 0.020), with intense hepatocyte and weak neutrophil staining. HMGB1 levels in hepatic venous blood correlated with graft steatosis (r = 0.497, P = 0.03) and peak postoperative alanine aminotransferase levels (r = 0.588, P = 0.008). Our results indicate that HMGB1 originates from the graft and is a marker of hepatocellular injury in human liver transplantation. Liver Transpl 14:1517,1525, 2008. © 2008 AASLD. [source] Impact of preoperative steroids administration on ischemia-reperfusion injury and systemic responses in liver surgery: A prospective randomized studyLIVER TRANSPLANTATION, Issue 6 2006Luca Aldrighetti Hepatic injury secondary to warm ischemia-reperfusion (I/R) injury and alterations in haemostatic parameters are often unavoidable events after major hepatic resection. The release of inflammatory mediator is believed to play a significant role in the genesis of these events. It has been suggested that preoperative steroid administration may reduce I/R injury and improve several aspects of the surgical stress response. The aim of this prospective randomized study was to investigate the clinical benefits on I/R injury and systemic responses of preoperatively administered corticosteroids. Seventy-six patients undergoing liver resection were randomized either to a steroid group or to a control group. Patients in the steroid group received preoperatively 500 mg of methylprednisolone. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, coagulation parameters, and inflammatory mediators, interleukin 6 and tumor necrosis factor alpha were compared between the 2 groups. Length of stay, and type and number of complications were recorded as well. Postoperative serum levels of ALT, AST, total bilirubin, and inflammatory cytokines were significantly lower in the steroid than in the control group at postoperative days 1 and 2. Changes in hemostatic parameters were also significantly attenuated in the steroid group. In conclusion, the incidence of postoperative complications in the steroid group tended to be significantly lower than the control group. It is of clinical interest that preoperative steroids administration before major surgery may reduce I/R injury, maintain coagulant/anticoagulant homeostasis, and reduce postoperative complications by modulating the inflammatory response. Liver Transpl 12:941,949, 2006. © 2006 AASLD. [source] Review article: the clinical role of anti-TNF, antibody treatment in Crohn's diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2000The recent licensing of anti-TNF, antibody treatment offers the potential to radically alter the course of severe Crohn's disease using genetically-engineered drugs directed against a specific inflammatory mediator. Controlled randomized trials have demonstrated clinical benefit associated with tissue healing in patients with active intestinal disease and fistulae, often when conventional therapies were unsuccessful. This therapy is expensive, however, and long-term efficacy and safety data are still awaited. This review considers the nature of this therapy and the current evidence for its clinical benefit and adverse effects. The treatment is also considered in the context of available immunosuppressive agents, with suggestions about its practical application. [source] Cyclic Adenosine Monophosphate Regulation of Ion Transport in Porcine Vocal Fold Mucosae,THE LARYNGOSCOPE, Issue 8 2008Mahalakshmi Sivasankar PhD Abstract Objectives/Hypothesis: Cyclic adenosine monophosphate (cAMP) is an important biological molecule that regulates ion transport and inflammatory responses in epithelial tissue. The present study examined whether the adenylyl cyclase activator, forskolin, would increase cAMP concentration in porcine vocal fold mucosa and whether the effects of increased cAMP would be manifested as a functional increase in transepithelial ion transport. Additionally, changes in cAMP concentrations following exposure to an inflammatory mediator, tumor necrosis factor-, (TNF,) were investigated. Study Design: In vitro experimental design with matched treatment and control groups. Methods: Porcine vocal fold mucosae (N = 30) and tracheal mucosae (N = 20) were exposed to forskolin, TNF,, or vehicle (dimethyl sulfoxide) treatment. cAMP concentrations were determined with enzyme-linked immunosorbent assay. Ion transport was measured using electrophysiological techniques. Results: Thirty minute exposure to forskolin significantly increased cAMP concentration and ion transport in porcine vocal fold and tracheal mucosae. However, 30-minute and 2-hour exposure to TNF, did not significantly alter cAMP concentration. Conclusions: We demonstrate that forskolin-sensitive adenylyl cyclase is present in vocal fold mucosa, and further, that the product, cAMP increases vocal fold ion transport. The results presented here contribute to our understanding of the intracellular mechanisms underlying vocal fold ion transport. As ion transport is important for maintaining superficial vocal fold hydration, data demonstrating forskolin-stimulated ion transport in vocal fold mucosa suggest opportunities for developing pharmacological treatments that increase surface hydration. [source] Serotonin content of normal and inflamed appendix: a possible role of serotonin in acute appendicitis,APMIS, Issue 11 2008MOHAMMAD VASEI The appendix is lined by a mucosa which has many neuroendocrine cells containing serotonin. Local release of serotonin can act as a mediator of inflammation. In this study we explored the serotonin content of the neuroendocrine cells of the appendixes removed for clinical diagnosis of appendicitis. Appendix specimens were divided into three groups: Acute appendicitis (AA), non-appendicitis (NA), and follicular hyperplasia (FH). Normal appendix specimens from patients undergoing elective abdominal surgery were used as the control group (NL). All sections were exposed to proteinase K, incubated with anti-serotonin, chromogranin A, and synaptophysin antibodies, and treated with the LSAB kit. Polygonal cells were seen within the crypt epithelium (enterochromaffin cell, EC) and within the lamina propria (subepithelial neuroendocrine cell, SNC). In AA, only 16 cases (64%) showed serotonin staining in non-destructed glands. There was a significant reduction in the number of ECs in AA compared to the FH (96%), NA (100%) and NL (100%) groups (P<0.001). Chromogranin and synaptophysin immunostaining also showed a significant reduction in the number of ECs in AA compared with the other three groups (P<0.001). SNC serotonin reactivity was lower in the AA group compared with the other groups (p<0.001). The inflamed appendix is markedly depleted of serotonin in the epithelium and lamina propria. Local serotonin release from ECs and SNCs in the appendix may act as an inflammatory mediator in appendicitis and is likely to be the source of raised blood serotonin in AA. [source] Genetic susceptibility to viral exposure may increase the risk of cerebral palsyAUSTRALIAN AND NEW ZEALAND JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Issue 3 2009Michael DJUKIC Aim: Cytokine polymorphisms may alter the fetal inflammatory response, increasing susceptibility to cerebral palsy (CP). This study investigates associations between selected inflammatory mediator and cytokine gene polymorphisms (Toll-like receptor-4 (TLR-4) Asp299Gly, interleukin-6 G-174C and interleukin-4 C-589T) and CP from 443 CP infants and 883 control infants. Results were correlated with viral nucleic acids in the same samples. Results: At all gestational ages (GA), TLR-4 was associated with a decreased risk of developing CP (homozygous/heterozygous odds ratio (OR) 0.70, 95% confidence interval (CI) 0.50,0.98) and interleukin (IL)-6 was associated with an increased risk of developing hemiplegia (OR 1.38, 95% CI 1.05,1.83). For infants born 32,36 weeks GA, there was a tenfold increase in the risk of quadriplegic CP with homozygous/heterozygous IL-6 (OR 10.42, 95% CI 1.34,80.82). Viral exposure in combination with IL-4 in preterm infants was associated with a fourfold increased risk of quadriplegia (homozygous/heterozygous OR 4.25, 95% CI 1.21,14.95). In very preterm infants, the absence of detectable viral exposure in combination with IL-4 decreased the risk of developing CP (homozygous/heterozygous OR 0.31, 95% CI 0.13,0.76). Conclusion: Polymorphisms in TLR-4 may be associated with a decreased risk of CP. Polymorphisms in IL-6 or IL-4 may act as susceptibility genes, in the presence of viral exposure, for the development of hemiplegic and quadriplegic CP. These associations require confirmation but they suggest a hypothesis for CP causation due to double jeopardy from neurotropic viral exposure and genetic susceptibility to infection. [source] High-quality crystals of human haematopoietic prostaglandin D synthase with novel inhibitorsACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2010Sachiko Takahashi Human haematopoietic prostaglandin D synthase (H-PGDS; EC 5.3.99.2) produces prostaglandin D2, an allergic and inflammatory mediator, in mast cells and Th2 cells. H-PGDS has been crystallized with novel inhibitors with half-maximal inhibitory concentrations (IC50) in the low nanomolar range by the counter-diffusion method onboard the Russian Service Module on the International Space Station. The X-ray diffraction of a microgravity-grown crystal of H-PGDS complexed with an inhibitor with an IC50 value of 50,nM extended to 1.1,Å resolution at 100,K using SPring-8 synchrotron radiation, which is one of the highest resolutions obtained to date for this protein. [source] Inhibition of calcium-calmodulin kinase restores nitric oxide production and signaling in submandibular glands of a mouse model of salivary dysfunctionBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2004Florencia Rosignoli Nitric oxide is an intracellular and diffusible messenger of neurotransmitters involved in salivary secretion, as well as an inflammatory mediator in salivary gland diseases. It is synthesized by three different isoforms of nitric oxide synthase (NOS), each subject to a fine transcriptional, post-transcriptional and/or post-translational regulation. Our purpose was to study the possible mechanisms leading to NOS downregulation in submandibular glands of normal mice and in the nonobese diabetic (NOD) mouse model of salivary dysfunction with lower NOS activity. NOS activity and cGMP accumulation were determined by radioassays in submandibular glands of both mice in the presence of the protein kinase inhibitors KN-93 and bisindolylmaleimide. NOS I mRNA and protein expression and localization were assessed by RT,PCR, Western blot and immunohistochemistry. A downregulatory effect of calcium,calmodulin kinase II (CaMK II) on NOS activity in submandibular glands of both NOD and BALB/c mice was observed. Our results are consistent with a physiological regulation of NOS activity by this kinase but not by PKC in normal BALB/c mice. They are also supportive of a role for CaMK II in the lack of detectable NOS activity in submandibular glands of NOD mice. KN-93 also restored cGMP accumulation in NOD submandibular glands. The downregulation of NOS in NOD mice seems to be mainly mediated by this kinase rather than the result of a lower expression or different cellular localization of the enzyme. It was not related to different substrate or cofactors availability either. British Journal of Pharmacology (2004) 143, 1058,1065. doi:10.1038/sj.bjp.0705952 [source] Non-lipooligosaccharide-mediated signalling via Toll-like receptor 4 causes fatal meningococcal sepsis in a mouse modelCELLULAR MICROBIOLOGY, Issue 3 2007Laura Plant Summary Meningococcal lipooligosaccharide (LOS) is a major inflammatory mediator of fulminant meningococcal sepsis and meningitis with disease severity correlating with circulating concentrations of LOS and proinflammatory cytokines. In this study we show that the proinflammatory response to live meningococci in a mouse model of sepsis involves TLR4, but can develop independently of the expression of LOS. This is supported by data showing that in vivo an isogenic LOS-deficient strain, lpxA, induced equivalent disease severity and similar proinflammatory responses as the serogroup C wild-type parent strain FAM20. This response was abolished in TLR4,/, mice, and neither the wild-type strain of meningococci nor the LOS-deficient mutant was able to cause fatal sepsis in these mice. Mouse survival correlated with low levels of cytokines and chemokines, the chemotactic complement factor C5a and neutrophil levels in blood at 24 h post infection. These data suggest that during meningococcal sepsis the recognition of one or more unidentified non-LOS component(s) by TLR4 is important in stimulating proinflammatory responses, and that fatality associated with meningococcal sepsis in mice is induced by the proinflammatory host response. [source] Paradoxical Hypertrichosis After Laser Therapy: A ReviewDERMATOLOGIC SURGERY, Issue 3 2010SHRADDHA DESAI MD BACKGROUND Laser hair removal is a safe and effective procedure for the treatment of unwanted body hair but is not exempt from side effects. A rare but significant adverse effect with this treatment modality is paradoxical hypertrichosis. OBJECTIVE To evaluate the potential etiologies, risk factors, related laser types, and treatment options for the development of excess hair after laser therapy. MATERIALS AND METHODS An analysis of previously published case studies and review articles along with our own experience was used to gather information regarding this phenomenon. RESULTS Paradoxical hypertrichosis has a low incidence, ranging from 0.6% to 10%, and most commonly occurs on the face and neck. All laser and light sources have the potential to cause hair induction, especially in individuals with darker skin types (III,VI); with dark, thick hair; and with underlying hormonal conditions. Possible causes include the effect of inflammatory mediators and subtherapeutic thermal injury causing induction of the hair cycle. Treatment for paradoxical hypertrichosis is laser therapy of the affected area. CONCLUSIONS Paradoxical hypertrichosis is a rare side effect of laser hair removal; the pathogenesis of this event remains widely unknown. We recommend further large-scale studies to investigate this effect. The authors have indicated no significant interest with commercial supporters. [source] Insulitis in type 2 diabetesDIABETES OBESITY & METABOLISM, Issue 2008M. Böni-Schnetzler Islets of patients with type 2 diabetes have the feature of an inflammatory process reflected by the presence of cytokines, immune cells, ,-cell apoptosis, amyloid deposits and fibrosis. Indeed, ,-cells from patients with type 2 diabetes display inflammatory markers, including increased interleukin (IL)-1, expression. Furthermore, increased islet-associated macrophages are observed in human type 2 diabetic patients and in most animal models of diabetes. Importantly, increased numbers of macrophages are detectable very early in high fat,fed mice islets, before the onset of diabetes. These immune cells are most likely attracted by islet-derived chemokines, produced in response to metabolic stress, and under the control of IL-1,. It follows that modulation of intra-islet inflammatory mediators, in particular IL-1,, may prevent insulitis in type 2 diabetes and therefore presents itself as a possible causal therapy with disease-modifying potential. [source] Ex vivo TCR-induced leukocyte gene expression of inflammatory mediators is increased in type 1 diabetic patients but not in overweight childrenDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2010Jaime S. Rosa Abstract Background Abnormal systemic concentrations of proinflammatory cytokines/chemokines have been implicated in the development of long-term cardiovascular complications in type 1 diabetes (T1DM) and obesity. Whether leukocyte white blood cell (WBC) gene expression of these proinflammatory mediators contributes to their increased systemic levels, however, remains unclear, especially in the pediatric patient populations. This study examines mRNA changes of 9 cytokines and chemokines in WBCs following ex vivo immunostimulation from 9 T1DM (13.4 ± 0.5 year, 4F/5 M), 23 overweight (OW, 12.3 ± 0.5 year, 10F/13M, BMI% 97.1 ± 0.5 and > 90.0), and 21 healthy (CL, 13.8 ± 0.7 year, 9F/12 M, BMI% 59.6 ± 4.6 and < 85.0) children. Methods All subjects had been maintained in euglycemic conditions for at least 90 min before blood draws. Whole blood was then sampled and incubated with anti-T-cell receptor (TCR) antibody or heat-aggregated IgG (HAG) to stimulate T-cell and Fc receptors (FcR), respectively. After lysis of leukocytes, mRNA levels of six tumor necrosis factor superfamily cytokines (TNFSF2, 5, 6, 7, 9, 14) and three chemokines (CCL8, 20, and CXCL10) were measured using RT-PCR. Results Following TCR stimulation, T1DM displayed significantly greater mRNA responses than CL for TNFSF5, 7, 9, and CCL8, and CXCL10; TNFSF9, CCL8, and CXCL10 were also significantly higher in T1DM than OW; no difference was observed between OW and CL. FcR stimulation induced similar responses across groups. Conclusions Leukocytes of T1DM children displayed exaggerated gene expression in response to ex vivo TCR induction of five key proinflammatory cytokines/chemokines. This elevated leukocyte gene expression may be one of the pathophysiological contributors to the development of vascular complications in T1DM. Copyright © 2009 John Wiley & Sons, Ltd. [source] Metabolic memory in diabetes,focus on insulinDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2005Derek LeRoith Abstract Large-scale clinical trials have demonstrated that metabolic control achieved early in the course of diabetes substantially reduces development and progression of diabetes and the associated microvascular complications. Additionally, prospective observational studies have demonstrated that atherogenic and inflammatory mediators are elevated even prior to the onset of diabetes and significantly contribute to subsequent development of macrovascular complications. Collectively, these data suggest that metabolic memories are stored early in the course of diabetes. We believe that insulin suppresses inflammation and also suppresses glucotoxicity and lipotoxicity (and the consequences thereof, such as the formation of advanced glycation end products and epigenetic phenomena), and thus has a pivotal and beneficial role. Comprehensive metabolic control, especially when instituted early, may alter the natural history of diabetic complications by affecting this metabolic memory. Thus, our overall goal is to understand in more detail the molecular mechanisms involved in these changes, thereby affording us opportunities to reduce the long-term effects of diabetes. Copyright © 2005 John Wiley & Sons, Ltd. [source] Assessment of physical fitness for esophageal surgery, and targeting interventions to optimize outcomesDISEASES OF THE ESOPHAGUS, Issue 7 2010C. Feeney SUMMARY This review examines how higher levels of physiological reserve and fitness can help the patient endure the demands of esophageal surgery. Lung function, body composition, cardiac function, inflammatory mediators and exercise performance are all determinants of fitness. Physical fitness, both as an independent risk factor and through its effect on other risk factors, has been found to be significantly associated with the risk of developing postoperative pulmonary complications (PPCs) in patients following esophagectomy. Respiratory dysfunction preoperatively poses the dominant risk of developing complications, and PPCs are the most common causes of morbidity and mortality. The incidence of PPCs is between 15 and 40% with an associated 4.5-fold increase in operative mortality leading to approximately 45% of all deaths post-esophagectomy. Cardiac complications are the other principal postoperative complications, and pulmonary and cardiac complications are reported to account for up to 70% of postoperative deaths after esophagectomy. Risk reduction in patients planned for surgery is key in attaining optimal outcomes. The goal of this review was to discuss the risk factors associated with the development of postoperative pulmonary complications and how these may be modified prior to surgery with a specific focus on the pulmonary complications associated with esophageal resection. There are few studies that have examined the effect of modifying physical fitness pre-esophageal surgery. The data to date would indicate a need to develop targeted interventions preoperatively to increase physical function with the aim of decreasing postoperative complications. [source] Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regeliiEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2009D. H. Kim Abstract Background, Celastrol, a quinone methide triterpenoid isolated from the Celastraceae family, exhibits various biological properties, including chemopreventive, antioxidant and neuroprotective effects. In this study, we showed that celastrol inhibits inflammatory reactions in macrophages and protects mice from skin inflammation. Materials and methods, Anti-inflammatory effects of celastrol (0,1 ,M) were examined in lipopolysaccharide (LPS)-stimulated RAW 264·7 macrophages. To investigate the effects of celastrol (0,50 ,g per mice) in vivo, activation of myeloperoxidase (MPO) and histological assessment were examined in the 12- O -tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear oedema model. Results, Our in vitro experiments showed that celastrol suppressed not only LPS-stimulated generation of nitric oxide and prostaglandin E2, but also expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW264·7 cells. Similarly, celastrol inhibited LPS-induced production of inflammatory cytokines, including tumour necrosis factor-, and interleukin-6. In an animal model, celastrol protected mice from TPA-induced ear oedema, possibly by inhibiting MPO activity and production of inflammatory cytokines. Conclusions, Our data suggest that celastrol inhibits the production of inflammatory mediators and is a potential target for the treatment of various inflammatory diseases. [source] Interferon-, in healthy subjects: selective modulation of inflammatory mediatorsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2001J. De Metz Background It is suggested that interferon-, (IFN-,), like other cytokines, is a mediator in the host inflammatory response, which could be of importance in the pathophysiology of sepsis. The role of IFN-, in human host inflammatory responses, however, has not been studied. Design In a placebo-controlled trial we studied the acute effects of IFN-, administration on host inflammatory mediators in healthy men: i.e. the cytokine/chemokine cascade system, acute-phase proteins, activation markers of the innate cellular immunity and coagulation/fibrinolysis parameters. Results IFN-, increased plasma levels of interleukin-6 (IL-6), IL-8 and IFN-,-inducible protein-10 (IP-10) (P < 0·05), but did not affect plasma levels of other cytokines (IL-4, IL-10, tumour necrosis factor-,, IL-12p40/p70). Plasma concentrations of C-reactive protein and secretory phospholipase A2 both increased (P < 0·05). Plasma levels of the leucocyte activation marker elastase-,1,antitrypsin complexes increased after IFN-, administration (P < 0·05), IFN-, increased the percentage of high-affinity Fc,-receptor (Fc,RI) -positive neutrophils (P < 0·05), but did not affect the mean fluorescence intensity of Fc,RI on neutrophils. Procoagulant and profibrinolytic effects of IFN-, were evidenced by increased plasma levels of prothrombin fragment F1 + F2, tissue-plasminogen activator and plasmin-,2,antiplasmin complexes (P < 0·05). Conclusion We conclude that IFN-, selectively affects host inflammatory mediators in humans. [source] Complement C5a regulates IL-17 by affecting the crosstalk between DC and ,, T cells in CLP-induced sepsisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010Ruonan Xu Abstract Complement 5a (C5a) and Interleukin-17 (IL-17) are two important inflammatory mediators in sepsis. Here we studied the mechanisms underlying regulation of IL-17 by anaphylatoxin C5a. We found that C5a blockade increased the survival rate of mice following cecal ligation and puncture (CLP)-induced sepsis and decreased IL-17 expression in vivo. IL-17 was secreted mainly by ,, T cells in this model. Importantly, our data suggest that C5a participates in the regulation of IL-17 secretion by ,, T cells. Dendritic cells (DC) were found to act as a "bridge" between C5a and ,, T cells in a mechanism involving IL-6 and transforming growth factor , (TGF-,). These results imply that C5a affects the crosstalk between DC and ,, T cells during sepsis development, and this may result in a large production of inflammatory mediators such as IL-17. [source] Dok protein family members are involved in signaling mediated by the type 1 Fc, receptorEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2003Jakub Abramson Abstract Aggregation of type 1 Fc, receptors (Fc,RI) on mast cells activates a biochemical cascade that culminates in secretion of inflammatory mediators, as well as in changes of cell morphology and adhesion properties. Some of the intracellular components involved in the early coupling events are still unidentified. Here we show that two adaptor proteins, downstream of tyrosine kinases (Dok)-1 and Dok-2, are involved in the Fc,RI coupling cascade in the rat mucosal-type mast cells of the RBL-2H3 line. Dok-1 is found to be constitutively associated with the Fc,RI, even in untreated cells, and this interaction is not affected by this receptor's aggregation. Both Dok forms undergo a fast and relatively long-term tyrosyl-phosphorylation. This modification of Dok-1 increases its association with RasGAP, suggesting that it is modulating Ras activity. Indeed, we further found that Fc,RI-mediated Ras/Raf1/Erk signaling as well as the de novo synthesis of TNF-, are markedly reduced in cells overexpressing Dok-1. Moreover, Fc,RI clustering causes both Dok-1 and Dok-2 to become docking sites for other signaling molecules including Nck, CrkL and Cas. The latter proteins have been implicated particularly in regulation of the actin-cytoskeletal reorganization. Hence Dok-1/Dok-2 may also be involved in the Fc,RI-stimulated processes of cytoskeleton rearrangement required for cell adhesion, membrane ruffling and exocytosis. [source] The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkersEUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2009M. Khademi Background:, Natalizumab affects systemic cytokine expressions and clinical course in relapsing,remitting multiple sclerosis (RRMS). We analyzed levels of inflammatory cytokines in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs), levels of matrix metalloproteinase (MMP)-9 and osteopontin (OPN) in CSF, and clinical outcome measures in 22 natalizumab-treated RRMS patients. Methods:, mRNA levels of cytokines in cells were detected with real-time RT-PCR. Protein levels of OPN and MMP-9 were measured by ELISA. Results:, Natalizumab reduced CSF cell counts (P < 0.0001). Tumor necrosis factor (TNF) and interferon-, (IFN-,) mRNAs were significantly increased in PBMCs. In contrast, expressions of IFN-, and interleukin (IL)-23 were decreased but IL-10 increased in the CSF cells. OPN and MMP-9 were reduced in the CSF. Patients being in remission at baseline showed the same deviations of mediators as those in relapse after natalizumab treatment. The open label clinical outcome measures were either stable or improved during therapy. Conclusions:, Natalizumab attenuates pro-inflammatory mediators intrathecally and the reduced pro-inflammatory milieu may allow increased production of the anti-inflammatory mediator IL-10. The increased systemic cytokines may impede the improvement of certain clinical measures like fatigue. The affected mediators seem to be sensitive to an immune-modifying treatment which could be used as biomarkers for this therapy. [source] | |||||||||||||||||||||||||||||||||||||||||||