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Inflammatory Damage (inflammatory + damage)
Selected AbstractsNeutropenia alters lung cytokine production in mice and reduces their susceptibility to pulmonary cryptococcosisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2003Abstract Neutrophils are generally considered to contribute to host defense through their potent microbicidal activity. However, there is accumulating evidence that neutrophils also have an important regulatory role in establishing the balance of Th1 and Th2 responses. This study investigated the role of neutrophils in defense against pulmonary Cryptococcus neoformans infection using neutrophil-depleted BALB/c mice generated by administering mAb RB6,8C5. Neutropenic mice with pulmonary infection survived significantly longer than control mice, but there was no difference between groups infected intravenously. On day,1 of infection, neutropenic mice had significantly smaller fungal burdens than control mice. On day,7, neutropenic mice had significantly higher lung concentrations of IL-10, TNF-,, IL-4, and IL-12 than control mice, but there was no difference in IFN-, and MCP-1 levels. Neutrophils influenced the outcome of cryptococcal infection in mice through mechanisms that did not involve a reduction in early fungal burden. The absence of neutrophils in lung tissue during the initial stages of infection appeared to alter the inflammatory response in a manner thatwas subsequently beneficial to the host. Higher levels of Th1- and Th2-associated cytokines in neutropenic mice could have simultaneously promoted a strong cellular response while reducing inflammatory damage to the lung. Our results support the emerging concept that neutrophils play an important function in modulating the development of the immune response. [source] Decreased iNOS synthesis mediates dexamethasone-induced protection of neurons from inflammatory injury in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2003Sabine Golde Abstract Brain inflammation is accompanied by transection of axons and death of neurons in the acute lesions of multiple sclerosis. We explored mechanisms of inflammatory damage to neurons in vitro using cocultures of rat embryonal cortical neurons with microglia activated by interferon-gamma (IFN,) and lipopolysaccharide (LPS). Previously, we have demonstrated that microglia are highly toxic to neurons and that nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) is necessary and sufficient to mediate this toxicity. Here, we show that addition of dexamethasone (1 µM) to activated cocultures provides effective neuroprotection. We demonstrate that dexamethasone down-regulates NO production of primary microglia by ,,50% and reduces steady-state iNOS protein and mRNA expression by ,,70%. These changes were reversed by the glucocorticoid receptor blocker RU-486. Furthermore, we analysed the stability of iNOS protein and show that whilst inhibitors of the proteasome blocked iNOS degradation they did not reverse the dexamethasone effect. Our results indicate that the main mechanism of corticosteroid activity on iNOS is reduction in protein synthesis, not destabilization as previously suggested. [source] Synthesis of Polymerizable Superoxide Dismutase Mimetics to Reduce Reactive Oxygen Species Damage in Transplanted Biomedical Devices,ADVANCED FUNCTIONAL MATERIALS, Issue 20 2008Charles Y. Cheung Abstract A new polymerizable superoxide dismutase (SOD) mimetic metalloporphyrin macromer was synthesized to minimize inflammatory damage associated with tissue transplantation and biomaterial implantation, such as the use of encapsulated pancreatic islets for the treatment of type I diabetes mellitus (TIDM). This functional SOD mimetic, Mn(III) Tetrakis[1-(3-acryloxy-propyl)-4-pyridyl] porphyrin (MnTPPyP-Acryl), was copolymerized and crosslinked with poly(ethylene glycol) diacrylate (PEGDA) to form hydrogel networks that may actively reduce reactive oxygen species (ROS) damage associated with biomaterial implantation. Solution phase activity assays with MnTPPyP-Acryl macromers showed comparable SOD activity to MnTMPyP, a non-polymerizable commercially available SOD mimetic. This work also describes the development of a new, simple, and inexpensive solid phase assay system that was developed to assess the activity of MnTPPyP-Acryl macromers polymerized within PEGDA hydrogels, which has the potential to fulfill an existing void with the biochemical tools available for testing other immobilized ROS antagonists. With this new assay system, hydrogels containing up to 0.25,mol% MnTPPyP-Acryl showed significantly higher levels of SOD activity, whereas control hydrogels polymerized with inactive TPPyP-Acryl macromers showed only background levels of activity. The potential for repeated use of such hydrogel devices to consistently reduce superoxide anion concentrations was demonstrated upon retention of ,100% SOD activity for at least 72,h post-polymerization. These results demonstrate the potential that polymerizable SOD mimetics may have for integration into medical devices for the minimization of inflammatory damage upon transplantation, such as during the delivery of encapsulated pancreatic islets. [source] Effect of heme oxygenase-1 induction by octreotide on TNBS-induced colitisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2007im Erbil Abstract Background and Aim:, Ulcerative colitis is a chronic inflammatory disease of the colon and rectum. Although the precise etiology of ulcerative colitis remains unknown, it is believed to involve an abnormal host response to endogenous or environmental antigens, genetic factors, and oxidative damage. The aim of the present study was to investigate whether heme oxygenase-1 (HO-1) induction by octreotide could protect against oxidative and inflammatory damage from induced colitis. Methods:, Rats received octreotide 50 µg/kg per day intraperitoneally for 5 days before 2,4,6 trinitrobenzene sulfonic acid (TNBS) solution administration and for 15 days following TNBS solution administration. Rats were killed on day 21, and colonic malondialdehyde (MDA) levels, glutathione (GSH) levels and HO-1 expression were measured. Nuclear factor (NF)-,B and HO-1 expression was evaluated by immunohistochemical examination of the colonic tissue. Results:, Rats with TNBS-induced colitis had significantly increased colonic MDA levels and HO-1 expression in comparison to the control group. Octreotide treatment was associated with increased HO-1 expression and GSH levels, but decreased MDA levels. Histopathological examination revealed that the intestinal mucosal structure was preserved in the octreotide-treated group. In addition, treatment with octreotide significantly increased HO-1 expression and decreased NF-,B expression by immunohistochemistry when compared to the TNBS-induced colitis group. Conclusion:, Octreotide appears to have protective effects against colonic damage in TNBS-induced colitis. This protective effect is, in part, mediated by modification of the inflammatory response and the induction of HO-1 expression. [source] Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke modelJOURNAL OF PINEAL RESEARCH, Issue 2 2004Zhong Pei Abstract:, Inflammatory response following cerebral ischemia/reperfusion plays a key pathogenic role in ischemic cerebral damage. Nitric oxide (NO), cyclooxygenase-2 (COX-2) and myeloperoxidase (MPO) are important inflammatory mediators. Neuronal NO synthase (nNOS) is a major initial source of excessive NO during ischemia/reperfusion. Induction of COX-2 and infiltration of polymorphonuclear cells expressing MPO are critical factors in delayed inflammatory damage. Previously, we demonstrated that administration of melatonin before ischemia significantly reduced the infarct volume in a rat middle cerebral artery occlusion (MCAO) stroke model. In this study, we examined the effect of pretreatment with melatonin at 5 mg/kg on the immunoreactivity (ir) for nNOS, COX-2, MPO, and glial fibrillary acidic protein (GFAP) at 24, 48, and 72 hr after right-sided endovascular MCAO for 1 hr in adult male Sprague,Dawley rats. Melatonin did not affect the hemodynamic parameters. When compared with rats with sham MCAO, ischemia/reperfusion led to an ipsilateral increase in cells with positive ir for nNOS (similar at all times) and in ir-GFAP (similar at all times). Ischemia/reperfusion led to appearance of cells with positive ir for COX-2 (greatest at 24 hr with a tendency to increase again at 72 hr) or MPO (greatest at 24 hr). A single dose of melatonin significantly lessened the ipsilateral increase in cells with positive ir for nNOS, COX-2 or MPO, but did not influence the ipsilateral change in ir-GFAP. Our results suggest that melatonin treatment mediates neuroprotection against ischemia/reperfusion injury partly via inhibition of the consequential inflammatory response. [source] Post inflammatory damage to the enteric nervous system in diverticular disease and its relationship to symptomsNEUROGASTROENTEROLOGY & MOTILITY, Issue 8 2009J. Simpson Abstract:, Some patients with colonic diverticula suffer recurrent abdominal pain and exhibit visceral hypersensitivity, though the mechanism is unclear. Prior diverticulitis increases the risk of being symptomatic while experimental colitis in animals increases expression of neuropeptides within the enteric nervous system (ENS) which may mediate visceral hypersensitivity. Our aim was to determine the expression of neuropeptides within the ENS in diverticulitis (study 1) and in patients with symptomatic disease (study 2). Study 1 , Nerves in colonic resection specimens with either acute diverticulitis (AD, n = 16) or chronic diverticulitis (CD, n = 16) were assessed for neuropeptide expression recording % area staining with protein gene product (PGP9.5), substance P (SP), neuropeptide K (NPK), pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and galanin. Study 2 , Seventeen symptomatic and 15 asymptomatic patients with colonic diverticula underwent flexible sigmoidoscopy and multiple peridiverticular mucosal biopsies. Study 1, Neural tissue, as assessed by PGP staining was increased to a similar degree in circular muscle in both AD and CD. The CD specimens showed significant increases in the immunoreactivity of SP, NPK and galanin in both mucosal and circular muscle layer compared with controls. Study 2 , Mucosal histology was normal and PGP9.5 staining was similar between groups however patients with symptomatic diverticular disease demonstrated significantly higher levels of SP, NPK, VIP, PACAP and galanin within the mucosal plexus. Patients with symptomatic diverticular disease exhibit increased neuropeptides in mucosal biopsies which may reflect resolved prior inflammation, as it parallels the changes seen in acute and chronic diverticulitis. [source] Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous systemNEUROPATHOLOGY, Issue 3 2002Payam Rezaie Periventricular leukomalacia (PVL) occurring in premature infants, represents a major precursor for neurological and intellectual impairment, and cerebral palsy in later life. The disorder is characterized by multifocal areas of necrosis found deep in the cortical white matter, which are often symmetrical and occur adjacent to the lateral ventricles. There is no known cure for PVL. Factors predisposing to PVL include birth trauma, asphyxia and respiratory failure, cardiopulmonary defects, premature birth/low birthweight, associated immature cerebrovascular development and lack of appropriate autoregulation of cerebral blood flow in response to hypoxic-ischemic insults. The intrinsic vulnerability of oligodendrocyte precursors is considered as central to the pathogenesis of PVL. These cells are susceptible to a variety of injurious stimuli including free radicals and excitotoxicity induced by hypoxic-ischemic injury (resulting from cerebral hypoperfusion), lack of trophic stimuli, as well as secondary associated events involving microglial and astrocytic activation and the release of pro-inflammatory cytokines TNF-, and IL-6. It is yet unclear whether activated astrocytes and microglia act as principal participants in the development of PVL lesions, or whether they are representatives of an incidental pathological response directed towards repair of tissue injury in PVL. Nevertheless, the accumulated evidence points to a pathological contribution of microglia towards damage. The topography of lesions in PVL most likely reflects a combination of the relatively immature cerebrovasculature together with a failure in perfusion and/or hypoxia during the greatest period of vulnerability occurring around mid-to-late gestation. Mechanisms underlying the pathogenesis of PVL have so far been related to prenatal ischemic injury to the brain initiated within the third trimester, which result in global cognitive and developmental delay and motor disturbances. Over the past few years, several epidemiological and experimental studies have implicated intrauterine infection and chorioamnionitis as causative in the pathogenesis of PVL. In particular, recent investigations have shown that inflammatory responses in the fetus and neonate can contribute towards neonatal brain injury and development-related disabilities including cerebral palsy. This review presents current concepts on the pathogenesis of PVL and emphasizes the increasing evidence for an inflammatory pathogenic component to this disorder, either resulting from hypoxic-ischemic injury or from infection. These findings provide the basis for clinical approaches targeted at protecting the premature brain from inflammatory damage, which may prove beneficial for treating PVL, if identified early in pathogenesis. [source] Wnt Pathway Regulation in Chronic Renal Allograft DamageAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009C. Von Toerne The Wnt signaling pathway, linked to development, has been proposed to be recapitulated during the progressive damage associated with chronic organ failure. Chronic allograft damage following kidney transplantation is characterized by progressive fibrosis and a smoldering inflammatory infiltrate. A modified, Fischer 344 (RT1lvl) to Lewis (RT1l) rat renal allograft model that reiterates many of the major pathophysiologic processes seen in patients with chronic allograft failure was used to study the progressive disease phenotype and specific gene product expression by immunohistochemistry and transcriptomic profiling. Central components of the Tgfb, canonical Wnt and Wnt-Ca2+ signaling pathways were significantly altered with the development of chronic damage. In the canonical Wnt pathway, Wnt3, Lef1 and Tcf1 showed differential regulation. Target genes Fn1, Cd44, Mmp7 and Nos2 were upregulated and associated with the progression of renal damage. Changes in the Wnt-Ca2+ pathway were evidenced by increased expression of Wnt6, Wnt7a, protein kinase C, Cam Kinase II and Nfat transcription factors and the target gene vimentin. No evidence for alterations in the Wnt planar cell polarity (PCP) pathway was detected. Overall results suggest cross talk between the Wnt and Tgfb signaling pathways during allograft inflammatory damage and present potential targets for therapeutic intervention. [source] Actions of glucocorticoid and their regulatory mechanisms in the ovaryANIMAL SCIENCE JOURNAL, Issue 2 2007Masafumi TETSUKA ABSTRACT Glucocorticoid (G) directly modulates ovarian functions through binding to G receptor. The actions of G are both agonistic and antagonistic depending on the developmental stage of follicles and corpora lutea (CL). During follicular maturation, G suppresses follicular differentiation by downregulating expression of P450 aromatase and luteinizing hormone (LH) receptor in granulosa cells. During ovulation, G protects the ovulatory follicle from inflammatory damage and promotes luteinization, ensuring a smooth transition of the follicle to CL. Throughout life the ovary is exposed to periodic and sporadic waves of G. The Ovary appears to cope with this situation by locally modulating levels of active G. The primary regulatory mechanism consists of two isoforms of 11,-hydroxysteroid dehydrogenase (11,HSD) that catalyze conversion between active and inactive G. During follicular maturation the levels of active G are suppressed by the dehydrogenase activity of 11,HSD, whereas during the ovulatory process, levels of active G are further increased by the oxo-reductase activity of 11,HSD. The expression of these enzymes is under the control of gonadotrpins and local regulatory factors such as cytokines, allowing the mechanism to act in coordination with major reproductive events. Thus the G system is an integral part of ovarian physiology, which ensures that the ovary experiences only beneficial effects of G. [source] | |||||||||||||