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Inflammatory Gene Expression (inflammatory + gene_expression)
Selected AbstractsProstaglandin E2 is activated by airway injury and regulates fibroblast cytoskeletal dynamics,THE LARYNGOSCOPE, Issue 7 2009Vlad C. Sandulache MD Abstract Objectives/Hypothesis: To characterize the activation of cyclooxygenase (COX)-2/prostaglandin (PG) E2 signaling during airway mucosal repair and its subsequent role during the wound healing process. Study Design: Prospective animal study. Methods: The subglottis was approached via cricothyroidotomy. Sham airways were closed, and wounded airways were subjected to laser injury and closed. Subglottic tissue was harvested at 12 hours, 24 hours, 48 hours, and 72 hours postinjury. Secretions were collected preoperatively and at time of sacrifice. Inflammatory gene expression was analyzed using quantitative reverse transcriptase polymerase chain reaction. Subglottic/tracheal explants were exposed to exogenous IL-1, in the presence or absence of COX inhibitors. Explant-produced PGE2 levels were assayed using enzyme linked immunoassays. Human airway fibroblast migration and collagen contraction were assayed in the presence or absence of prostaglandin E2. Results: Laser injury triggers a rapid, dose-dependent increase in mucosal IL-1, and COX-2 gene expression, with an anatomical distribution proportional to the distance from the site of injury. Gene upregulation correlates with dose-dependent increases in PGE2 mucosal secretion levels. Ex vivo analysis indicates IL-1, is responsible for the activation of the COX-2 / PGE2 pathway. Prostaglandin E2 differentially inhibits airway fibroblast migration and contraction in a specific, dose-dependent manner. Conclusions: PGE2 is activated during mucosal inflammation and acts to decrease fibroplastic activity in the mucosal wound bed. During subglottic stenosis (SGS) development, the levels of PGE2 generated in response to injury may be insufficient to blunt the intrinsically fibroplastic phenotype of SGS fibroblasts, resulting in excessive scarring. Laryngoscope, 2009 [source] Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditionsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2009Lorena Perrone Chronic hyperglycemia and activation of receptor for advanced glycation end products (RAGE) are known risk factors for microvascular disease development in diabetic retinopathy. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin (TRX), plays a causative role in diabetes and its vascular complications. Herein we investigate whether HG and RAGE induce inflammation in rat retinal endothelial cells (EC) under diabetic conditions in culture through TXNIP activation and whether epigenetic mechanisms play a role in inflammatory gene expression. We show that RAGE activation by its ligand S100B or HG treatment of retinal EC induces the expression of TXNIP and inflammatory genes such as Cox2, VEGF-A, and ICAM1. TXNIP silencing by siRNA impedes RAGE and HG effects while stable over-expression of a cDNA for human TXNIP in EC elevates inflammation. p38 MAPK-NF-,B signaling pathway and histone H3 lysine (K) nine modifications are involved in TXNIP-induced inflammation. Chromatin immunoprecipitation (ChIP) assays reveal that TXNIP over-expression in EC abolishes H3K9 tri-methylation, a marker for gene inactivation, and increases H3K9 acetylation, an indicator of gene induction, at proximal Cox2 promoter bearing the NF-,B-binding site. These findings have important implications toward understanding the molecular mechanisms of ocular inflammation and endothelial dysfunction in diabetic retinopathy. J. Cell. Physiol. 221: 262,272, 2009. © 2009 Wiley-Liss, Inc [source] Cyclic GMP phosphodiesterase inhibition alters the glial inflammatory response, reduces oxidative stress and cell death and increases angiogenesis following focal brain injuryJOURNAL OF NEUROCHEMISTRY, Issue 3 2010Paula Pifarré J. Neurochem. (2010) 112, 807,817. Abstract Recent evidence obtained in cultured glial cells indicates that cGMP-mediated pathways regulate cytoskeleton dynamics, glial fibrillary acidic protein expression and motility in astrocytes, as well as inflammatory gene expression in microglia, suggesting a role in the regulation of the glial reactive phenotype. The aim of this work was to examine if cGMP regulates the glial inflammatory response in vivo following CNS damage caused by a focal cryolesion onto the cortex in rats. Results show that treatment with the cGMP phosphodiesterase inhibitor zaprinast (10 mg/kg i.p.) 2 h before and 24 and 48 h after the lesion results 3 days post-lesion in notably enhanced astrogliosis manifested by increased glial fibrillary acidic protein immunoreactivity and protein levels around the lesion. In contrast, zaprinast decreased the number of round/ameboid lectin-positive cells and the expression of the activated microglia/macrophage markers Iba-1 and CD11b indicating decreased recruitment and activation of these cells. This altered inflammatory response is accompanied by a decrease in protein oxidative stress, apoptotic cell death and neuronal degeneration. In addition, zaprinast enhanced angiogenesis in the lesioned cortex probably as a result of vascular endothelial growth factor expression in reactive astrocytes. These results suggest that regulation of the glial inflammatory response may contribute to the reported neuroprotective effects of cGMP-phosphodiesterase inhibitors in brain injury. [source] Noradrenergic depletion potentiates ,-amyloid induced cortical inflammation: implications for Alzheimer's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 2002D. L. Feinstein Degeneration of locus ceruleus (LC) neurons and reduced levels of noradrenaline (NA) in LC projection areas is a well known feature of Alzheimer's disease (AD); however, the consequences of those losses are not clear. Since inflammatory mediators contribute to AD pathogenesis, and since NA can suppress inflammatory gene expression, we tested if LC loss influenced brain inflammatory gene expression elicited by amyloid , (A,). Adult rats were injected with the selective neurotoxin DSP4 to induce LC death, and subsequently injected in cortex with A, (aggregated 1,42 peptide). DSP4-treatment potentiated the A,-dependent induction of inflammatory nitric oxide synthase (iNOS), IL-1, and IL6 expression compared to control animals. In contrast, the induction of cyclooxygenase-2 expression was not modified by DSP4-treatment. In control animals, injection of A, induced iNOS primarily in microglial cells, while in DSP4-treated animals iNOS was localized to neurons, as is observed in AD brains. Injection of A, increased IL-1, expression initially in microglia, and at later times in astrocytes, and expression levels were greater in DSP4 treated animals than controls. The potentiating effects of DSP4-treatment on iNOS and IL-1, expression were attenuated by coinjection with NA or the ,-adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NA depletion augment inflammatory responses to A,, and suggest that LC loss in AD is permissive for increased inflammation and neuronal cell death. [source] Melatonin decreases TLR3-mediated inflammatory factor expression via inhibition of NF-,B activation in respiratory syncytial virus-infected RAW264.7 macrophagesJOURNAL OF PINEAL RESEARCH, Issue 1 2008Sheng-Hai Huang Abstract:, Double-stranded (ds) RNA has been identified as a ligand for Toll-like receptor 3 (TLR3). Respiratory syncytial virus (RSV), a single-stranded RNA virus and a major respiratory pathogen and pneumovirus in human infants pathogenesis of which relies on early inflammatory and immune events of the host in response to RSV, could be recognized by TLR3 sensing viral dsRNA produced during replication. The downstream signaling pathway from TLR3 leads to activation of IFN regulatory factor (IRF)-3 and/or NF-,B and subsequent expression of numerous proinflammatory factors. Melatonin (MT) is an effective regulator of the immune system. To determine the molecular mechanisms responsible for the suppressive effect of MT on RSV infection, we analyzed signaling molecules involved in the TLR3-mediated activation of inflammatory factors in macrophages infected with RSV and the modulatory role of MT on these mediators. We report that RSV infection of RAW264.7 macrophages time-dependently stimulate the rapid activation of TLR3 and NF-,B, as well as subsequent NF-,B-dependent gene expression such as those encoding TNF-, and inducible nitric oxide synthase. Moreover, we demonstrate that MT decreased TLR3-mediated downstream gene expression in RSV-infected macrophages in a dose- and time-dependent manner, and that MT inhibition of NF-,B activity seemed to be the key event required to explain the reduction in inflammatory gene expression caused by MT. But MT did not influence TLR3 at either the protein or mRNA level or MyD88 transcription. These results could be related to the beneficial immunoregulatory role of MT in RSV-infected macrophages and address the possible therapeutic potential of this indoleamine in human RSV diseases. [source] Induction of CCR2-dependent macrophage accumulation by oxidized phospholipids in the air-pouch model of inflammationARTHRITIS & RHEUMATISM, Issue 5 2009Alexandra Kadl Objective Macrophages are key players in the pathogenesis of rheumatoid synovitis as well as in atherosclerosis. To determine whether atherogenic oxidized phospholipids potentially contribute to synovial inflammation and subsequent monocyte/macrophage recruitment, we examined the effects of oxidized 1- palmitoyl-2-arachidonoyl- sn -3-glycero-phosphorylcholine (OxPAPC) on chemokine expression and leukocyte recruitment in a facsimile synovium in vivo using the murine air-pouch model. Methods Air pouches were raised by 2 injections of sterile air, and inflammation was induced by injecting either lipopolysaccharide (LPS) or OxPAPC into the pouch lumen. Inflammation was assessed by analysis of inflammatory gene expression using reverse transcription,polymerase chain reaction or immunohistochemical analysis, and leukocytes were quantified in the lavage fluid and in the pouch wall after staining with Giemsa or after enzymatic digestion followed by fluorescence-activated cell sorter analysis. Results Application of OxPAPC resulted in selective recruitment of monocyte/macrophages into the air-pouch wall, but not in the lumen. In contrast, LPS induced both monocyte and neutrophil accumulation in the pouch lumen as well as in the wall. LPS, but not OxPAPC, induced the expression of adhesion molecules E-selectin, P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. OxPAPC increased the expression of the CCR2 ligands monocyte chemotactic protein 1 (MCP-1), MCP-3, and MCP-5, as well as RANTES and growth-related oncogene , (GRO,), while it down-regulated the expression of CCR2 on macrophages. Moreover, oxidized phospholipid,induced macrophage accumulation was abrogated in CCR2,/, mice. Conclusion These data demonstrate that oxidized phospholipids trigger a type of inflammatory response that leads to selective macrophage accumulation in vivo, a process relevant for the pathogenesis of chronic inflammatory rheumatic diseases. [source] Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium: Regulation of synovial proliferation and inflammatory gene expressionARTHRITIS & RHEUMATISM, Issue 3 2006Masayasu Kitano Objective Sphingosine 1-phosphate (S1P) is involved in various pathologic conditions and has been implicated as an important mediator of angiogenesis, inflammation, cancer, and autoimmunity. This study was undertaken to examine the role of S1P/S1P1 signaling in the pathogenesis of rheumatoid arthritis (RA). Methods We examined S1P1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase,polymerase chain reaction and Western blotting. We also performed S1P1 immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of S1P on proliferation by WST-1 assay, and its effects on tumor necrosis factor , (TNF,), or interleukin-1, (IL-1,),induced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production in RA synoviocytes and MH7A cells by Western blotting and enzyme-linked immunosorbent assay, respectively. Finally, we examined whether these effects of S1P were sensitive to pertussis toxin (PTX), an inhibitor of the Gi/Go proteins. Results S1P1 mRNA and protein were detected in RA synoviocytes and MH7A cells. S1P1 was more strongly expressed in synovial lining cells, vascular endothelial cells, and inflammatory mononuclear cells of RA synovium compared with OA synovium. S1P increased the proliferation of RA synoviocytes and MH7A cells. S1P alone significantly enhanced COX-2 expression and PGE2 production. Moreover, S1P enhanced expression of COX-2 and production of PGE2 induced by stimulation with TNF, or IL-1, in RA synoviocytes and MH7A cells. These effects of S1P were inhibited by pretreatment with PTX. Conclusion These findings suggest that S1P signaling via S1P receptors plays an important role in cell proliferation and inflammatory cytokine,induced COX-2 expression and PGE2 production by RA synoviocytes. Thus, regulation of S1P/S1P1 signaling may represent a novel therapeutic target in RA. [source] Manipulation of the small intestine as a cause of the increased inflammatory response after open compared with laparoscopic surgery,,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 2 2006N. Hiki Background: Laparoscopic surgery of the gastrointestinal tract involves a reduced immune response compared with open surgery. The aim of this study was to assess manual handling of the gut in open procedures as the principal cause of the enhanced immune response. Methods: Eighteen Landrace pigs underwent gastrectomy by three different methods: conventional open wound with bowel manipulation, laparoscopically assisted gastrectomy, and gastrectomy without manipulation using a combination of open wound and laparoscopic surgical devices. Local inflammatory changes were assessed by ascites formation, intestinal adhesion development and intestinal inflammatory gene expression. Associated systemic inflammatory changes were determined by measuring portal and systemic plasma endotoxin levels, plasma inflammatory cytokine levels, liver inflammatory gene expression and transaminase levels. Results: Significantly more postoperative intra-abdominal fluid and adhesions were seen in the open group. The expression of inflammatory cytokines was significantly greater in the intestine and liver in the open group. Portal and systemic levels of endotoxin, inflammatory cytokines and transaminases were also higher. Conclusion: Manual handling of organs during gastrectomy is an important contributor to the molecular and humoral inflammatory response to surgery, supporting the use of minimally invasive techniques in gastrointestinal surgery. Copyright © 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] | |||||||||||||