Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon (IFN)-gamma-inducing factor was previously termed interleukin (IL)-18. Although IL-12 is also an IFN-gamma-inducing factor, the activity of IL-18 (but not IL-12) in models of sepsis and death is dependent on the intracellular cysteine protease IL-1beta converting enzyme (caspase-1). Caspase-1 is required for cleavage of the inactive precursor form of IL-18 into an active cytokine, and caspase-1-deficient mice are resistant to lethal endotoxemia. The absence of IFN-gamma (but not IL-1beta) in caspase-1-deficient mice is responsible for this resistance. However, the role of IFN-gamma in murine defense against gram-negative infection is inconsistent. Mice deficient in IFN-gamma are not resistant to lethal endotoxemia but are resistant when treated with neutralizing antibodies to IL-18 and challenged with a lethal injection of some endotoxins. Anti-IL-18 treatment also reduces neutrophil accumulation in liver and lungs. Neutralizing IL-18 with the IL-18 binding protein protects mice against endotoxin- and ischemia-induced hepatic damage. Thus, blockade of IL-18 appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.
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PMID:Interleukin-18 and host defense against infection. 1279 54

The specter of bioterrorism employing genetically engineered Rickettsia resistant to all antibiotics should reawaken the world's desire to elucidate the pathogenesis of typhus and spotted fever rickettsioses in a search for mechanisms vulnerable to interdiction. The pathogenetic sequence includes rickettsial entry into the dermis, hematogenous dissemination to vascular endothelial cells (most critically in brain and lungs), increased vascular permeability, edema, and immunity mediated by NK cells, IFN-gamma, TNF-alpha, RANTES, antibodies, and cytotoxic T lymphocytes. Silverman has demonstrated the role of reactive oxygen species (ROS) produced by R. rickettsii-infected endothelial cells in peroxidative damage to cell membranes in vitro, and Heinzen has described actin-based rickettsial intracellular mobility and intercellular spread. At this point the availability of sequences of rickettsial genomes and excellent animal models of rickettsioses have yielded insufficient progress towards the identification of rickettsial virulence factors and knowledge of the importance of injury mediated by ROS, phospholipase A(2), protease(s) or other mechanisms in vivo. Attention to the rickettsiosis-associated procoagulant state led to determination that hemostatic mechanisms largely prevent major hemorrhage without disseminated intravascular coagulation or thrombosis-mediated ischemia. Particularly lacking is knowledge of early events in vivo at the portal of entry in skin (or lung), of the effects of the inoculum medium (arthropod saliva or feces), mediators produced by infected endothelium under conditions of flow and of the contributions in vivo of immune effectors to pathology, of the role of apoptosis in rickettsial infection, and of the endothelial cell alterations that account for increased vascular permeability. The host cell receptor for the Rickettsia ligand and the mechanism of rickettsial escape from the phagosome need to be elucidated.
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PMID:Pathogenic mechanisms of diseases caused by Rickettsia. 1286 May 94

Infections are a leading cause of death in stroke patients. In a mouse model of focal cerebral ischemia, we tested the hypothesis that a stroke-induced immunodeficiency increases the susceptibility to bacterial infections. 3 d after ischemia, all animals developed spontaneous septicemia and pneumonia. Stroke induced an extensive apoptotic loss of lymphocytes and a shift from T helper cell (Th)1 to Th2 cytokine production. Adoptive transfer of T and natural killer cells from wild-type mice, but not from interferon (IFN)-gamma-deficient mice, or administration of IFN-gamma at day 1 after stroke greatly decreased the bacterial burden. Importantly, the defective IFN-gamma response and the occurrence of bacterial infections were prevented by blocking the sympathetic nervous system but not the hypothalamo-pituitary-adrenal axis. Furthermore, administration of the beta-adrenoreceptor blocker propranolol drastically reduced mortality after stroke. These data suggest that a catecholamine-mediated defect in early lymphocyte activation is the key factor in the impaired antibacterial immune response after stroke.
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PMID:Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. 3162 20

Nitric oxide, produced in macrophages by the high output isoform inducible NO synthase (iNOS), is associated with cytotoxic effects and modulation of Th1 inflammatory/immune responses. Ischemia and reperfusion lead to generation of high NO levels that contribute to irreversible tissue damage. Ischemia and reperfusion, as well as their in vitro simulation by hypoxia and reoxygenation, induce the expression of iNOS in macrophages. However, the molecular regulation of iNOS expression and activity in hypoxia and reoxygenation has hardly been studied. We show in this study that IFN-gamma induced iNOS protein expression (by 50-fold from control, p < 0.01) and nitrite accumulation (71.6 +/- 14 micro M, p < 0.01 relative to control), and that hypoxia inhibited NO production (7.6 +/- 1.7 micro M, p < 0.01) without altering iNOS protein expression. Only prolonged reoxygenation restored NO production, thus ruling out the possibility that lack of oxygen, as a substrate, was the cause of hypoxia-induced iNOS inactivation. Hypoxia did not change the ratio between iNOS monomers and dimers, which are essential for iNOS activity, but the dimers were unable to produce NO, despite the exogenous addition of all cofactors and oxygen. Using immunoprecipitation, mass spectroscopy, and confocal microscopy, we demonstrated in normoxia, but not in hypoxia, an interaction between iNOS and alpha-actinin 4, an adapter protein that anchors enzymes to the actin cytoskeleton. Furthermore, hypoxia caused displacement of iNOS from the submembranal zones. We suggest that the intracellular localization and interactions of iNOS with the cytoskeleton are crucial for its activity, and that hypoxia inactivates iNOS by disrupting these interactions.
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PMID:Hypoxia inactivates inducible nitric oxide synthase in mouse macrophages by disrupting its interaction with alpha-actinin 4. 1296 Mar 52

It was previously reported that ischemia-reperfusion injury initiates an inflammatory response and may significantly affect the transplanted organ function. The aim of this study was to assess changes of intragraft cytokine mRNA expression in kidneys after cold ischemia (CI) and following reperfusion. We examined mRNA of a product of activated T lymphocytes (IFN-gamma) and a monocyte product (IL-6). Eleven kidneys were transplanted after CI time ranging from 16 to 39 hours. Renal needle core biopsies were obtained from donors after cold ischemia and approximately after 20 minutes of reperfusion. Tubular and glomerular expression of IFN-gamma and IL-6 mRNA were assessed using semiquantitative evaluation of the RT-PCR in situ. After reperfusion an intense increase of IL-6 mRNA expression was observed in four specimens, a slight increase was noticed in five specimens, and a very slight decrease in two specimens. Changes in IL-6 mRNA expression were limited only to tubules. In contrast, the glomerular and tubular mRNA expression of IFN-gamma and glomerular of IL-6 remained stable. Mean CI time for patients with an intense increase was higher than for patients with a slight increase and with the decrease of IL-6 mRNA expression (32.0 +/- 6.8 vs 25.2 +/- 7.3 and 26.0 +/- 5.7 hours). Our results suggest that early inflammatory changes at the time of implantation of renal allografts depends mainly on monocyte/macrophage-associated products. The observed intensity of their expression in tubules was connected to longer CI time.
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PMID:Cytokine gene expression in kidney allograft donor biopsies after cold ischemia and reperfusion using in situ RT-PCR analysis. 1452 73

Leukocytes have been implicated in ischemia-reperfusion (IR) injury of the lung, but the individual role of T cells has not been explored. Recent evidence in mice suggests that T cells may play a role in IR injury. Using a syngeneic (Lewis to Lewis) rat lung transplant model, we observed that recipient CD4(+) T cells infiltrated lung grafts within 1 h of reperfusion and up-regulated the expression of CD25 over the ensuing 12 h. Nude rats (rnu/rnu) and heterozygous rats (rnu/+) were used to determine the role of T cells in IR injury. No significant difference in lung function was observed between nude and heterozygous recipient rats after 2 h of reperfusion. However, after 12 h of reperfusion, recipient nude rats had significantly higher oxygenation and lower peak airway pressure than recipient heterozygous rats. This was associated with significantly lower levels of IFN-gamma in transplanted lung tissue of recipient nude rats. Reconstitution of recipient nude rats with T cells from heterozygous rats restored IR injury after 12 h of reperfusion. The effect of T cells was independent of neutrophil recruitment and activation in the transplanted lung. These results demonstrate that recipient T cells are activated and mediate IR injury during lung transplantation in rats.
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PMID:Recipient T cells mediate reperfusion injury after lung transplantation in the rat. 1460 95

Ischemia-reperfusion (I/R) injury occurs as a result of restoring blood flow to previously hypoperfused vessels or after tissue transplantation and is characterized by inflammation and microvascular occlusion. We report here that 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester (ATL146e), a selective agonist of the A(2A) adenosine receptor (A(2A)AR), profoundly protects mouse liver from I/R injury when administered at the time of reperfusion, and protection is blocked by the antagonist ZM241385. ATL146e lowers liver damage by 90% as assessed by serum glutamyl pyruvic transaminase and reduces hepatic edema and MPO. Most protection remains if ATL146e treatment is delayed for 1 h but disappears when delayed for 4 h after the start of reperfusion. In mice lacking the A(2A)AR gene, protection by ATL1465e is lost and ischemic injury of short duration is exacerbated compared with wild-type mice, suggesting a protective role for endogenous adenosine. I/R injury causes induction of hepatic transcripts for IL-1alpha, IL-1beta, IL-1Ra, IL-6, IL-10, IL-18, INF-beta, INF-gamma, regulated on activation, normal T cell expressed, and presumably secreted (RANTES), major intrinsic protein (MIP)-1alpha, MIP-2, IFN-gamma-inducible protein (IP)-10, and monocyte chemotactic protein (MCP)-1 that are suppressed by administering ATL146e to wild-type but not to A(2A)AR knockout mice. RANTES, MCP-1, and IP-10 are notable as induced chemokines that are chemotactic to T lymphocytes. The induction of cytokines may contribute to transient lymphopenia and neutrophilia that occur after liver I/R injury. We conclude that most damage after hepatic ischemia occurs during reperfusion and can be blocked by A(2A)AR activation. We speculate that inhibition of chemokine and cytokine production limits inflammation and contributes to tissue protection by the A(2A)AR agonist ATL146e.
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PMID:Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. 1471 20

Liver injury induced by ischemia/reperfusion (I/R) is the prime factor in delayed or loss graft function following transplantation. CD4+ T lymphocytes are key cellular mediators of antigen-independent inflammatory response triggered by I/R. We attempted to modulate rat liver I/R injury by targeted gene therapy with CD40Ig, which blocks the CD40-CD154 costimulation pathway. One hundred percent of Ad-CD40Ig-pretreated orthotopic liver transplants (OLTs) subjected to 24 h of cold (4 degrees C) ischemia survived > 14 days (vs 50% in untreated/Ad-beta-gal groups). Ad-CD40Ig treatment decreased sGOT levels and depressed neutrophil infiltration, compared with controls. These functional data correlated with histological Suzuki's grading of hepatic injury, which in untreated/Ad-beta-gal groups showed severe necrosis (> 60%) and moderate to severe sinusoidal congestion; the Ad-CD40Ig-pretreated group revealed minimal sinusoidal congestion/necrosis. Unlike in controls, OLT expression of mRNA coding for IL-2/IFN-gamma remained depressed, whereas that of IL-4/IL-13 reciprocally increased in the Ad-CD40Ig group. Ad-CD40Ig reduced frequency of TUNEL+ cells and pro-apoptotic Caspase-3, but enhanced antioxidant HO-1 and anti-apoptotic Bcl-2/Bcl-xl expression. Thus, prolonged blockade of CD40-CD154 by CD40Ig exerts potent cytoprotection against hepatic I/R injury. These results provide the rationale for a novel gene therapy approach to maximize the organ donor pool through the safer use of liver transplants exposed to prolonged cold ischemia.
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PMID:Gene therapy for liver transplantation using adenoviral vectors: CD40-CD154 blockade by gene transfer of CD40Ig protects rat livers from cold ischemia and reperfusion injury. 1474 76

Giant cell arteritis (GCA), a vasculitis that targets medium- and large-size arteries, is ranked as a medical emergency because of its potential to cause blindness and stroke. The typical lesions, granulomas in the vessel wall, are formed by IFN-gamma-producing CD4+ T cells and macrophages. CD4+ T cells undergo in situ activation in the adventitia, where they interact with indigenous dendritic cells. Tissue injury is mediated by several distinct sets of macrophages that are committed to diverse effector functions. The dominant tissue injury in the media results from oxidative stress and leads to smooth muscle cell apoptosis and nitration of endothelial cells. Macrophage-derived growth factors are instrumental in driving the response-to-injury program of the artery that causes intimal hyperplasia and vessel occlusion. Clinical manifestations are those of tissue ischemia or a syndrome of exuberant systemic inflammation. The vascular and the systemic components of GCA contribute differentially to the disease, leading to distinct clinical phenotypes of this arteritis. Immunologically most interesting is polymyalgia rheumatica, in which the systemic component is combined with aborted vasculitis, suggesting a role for artery-specific tolerance mechanisms.
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PMID:Immunopathways in giant cell arteritis and polymyalgia rheumatica. 1487 49

Plasma levels of substance P (SP) and neurokinin A (NKA) tachykinin and of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) cytokines were assayed in plasma obtained from peripheral blood of 19 patients presenting with stable chronic coronary stenosis and 12 patients with acute coronary syndrome (ACS). Plasma samples were obtained before, during, and after percutaneous coronary intervention (PCI) consisting of implantation of a metallic stent. Fourteen healthy subjects without any evident risk factors for coronary artery disease (CAD) were also included for comparison at basal time. We found that plasma levels of both IFN-gamma and TNF-alpha were significantly higher in patients with chronic or acute CAD than those in control subjects at the time of presentation. NKA and IFN-gamma levels were also significantly increased in ACS patients compared with those in patients with stable disease. The analysis performed during and after PCI revealed that IFN-gamma levels increased 15 min after stent implantation in both chronic and ACS patients and that TNF-alpha levels increased in chronic patients only compared to basal values. In addition, a significant decrease of both NKA and SPA levels 48 h after the end of the revascularization procedure was observed in ACS patients. These data suggest that modulation of tachykinin and/or cytokine release with proinflammatory activity in chronic or acute cardiac ischemia and during following coronary stenting might play an important role in heart tissue damage and in long-term inflammatory complications of PCI.
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PMID:Modulation of tachykinin and cytokine release in patients with coronary disease undergoing percutaneous revascularization. 1520 84


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