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

We and others have proposed that cytokine-stimulated nitric oxide (NO) production is responsible for reversible myocardial depression in sepsis, trauma and ischemia. An effect of NO on cardiac sarcolemmal L-type calcium channels has also recently been proposed. The spontaneous beating rate of neonatal cardiac myocytes is regulated by the sarcolemmal L-type calcium channel. Accordingly, we sought to determine if cytokine-stimulated NO production could also regulate beating rates of neonatal cardiac myocytes. Treatment of neonatal rat cardiac myocytes with TNF, IL-1, IL-6, 10(-5)M NMA, or 10(-3)M NMA significantly enhanced spontaneous beating rates compared to untreated myocytes in serum-free media for 48 hours (p < or = .01; n = 12 for each). Only IL-1 treatment resulted in significant nitrite levels vs. control over 48 hours (4.2 +/- 0.7 vs. 0.3 +/- 0.2 nmoles/1.25 x 10(-5) cells, respectively) (n = 12). Nitrite production by IL-1 was inhibited by 10(-3)M NMA but not 10(-5)M NMA (0.3 +/- 0.2 vs. 4.1 +/- 0.6 nmoles; p < .01; n = 12). The addition of 10(-5)M NMA to TNF, IL-1, and IL-6 did not alter the effect of the cytokines on the spontaneous beating rates of the cardiac cells (p < or = .01; n = 12 for each). These results strongly suggest that cytokines and NMA affect cardiac myocyte spontaneous beating rates through mechanisms independent of NO.
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PMID:Chronotropic effects of cytokines and the nitric oxide synthase inhibitor, L-NMMA, on cardiac myocytes. 752 6

Data from recent studies suggest that donor fasting imparts a beneficial effect on the viability of transplanted hepatic allografts. Because starvation may temporarily inactivate Kupffer cells, and because these cells are the likely mediators of liver injury after prolonged preservation-reperfusion, the purpose of this study is to establish a link between improved organ viability and Kupffer cell inactivation caused by donor allograft fasting. In an in vivo rat liver transplant model, 48 hours of donor fasting (1) improved allograft viability, (2) significantly decreased Kupffer cell phagocytosis, and (3) significantly decreased cytokine (tumor necrosis factor [TNF]) production postrevascularization. These data validate work from previous studies demonstrating that donor fasting improves allograft viability and furthermore support our previous research implicating activation of Kupffer cells as a causative agent of cold ischemia-preservation injury.
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PMID:Inactivation of Kupffer cells after prolonged donor fasting improves viability of transplanted hepatic allografts. 755 76

Extravasation of leukocytes at sites of ischemia may mediate tissue injury. To determine how leukocyte accumulation may be induced by ischemia, effects of hypoxia on basal neutrophil expression of adhesion and activation receptors were examined. Effects of hypoxia upon preactivated cells were also studied. To determine whether regulation of expression is dependent on oxygen availability or on mitochondrial respiration, the effects of physical hypoxia (substitution of O2 by nitrogen) were compared with those of chemical hypoxia with sodium cyanide (NaCN). Leukocytes in whole blood (eight volunteers) were exposed either to hypoxia alone or to priming concentrations of lipopolysaccharide (LPS, 1 microgram/ml) followed by chemical hypoxia (NaCN, 1 mM) or physical hypoxia (PO2 of 1-10 torr) for various time intervals. Room air was controlled and hypoxic cells were labeled with fluorescent monoclonal antibodies to integrins CD18 and CD11b or to the 55-kDa TNF alpha cell surface receptor (TNFR). Receptor concentrations were measured by flow cytometry. Data were analyzed by ANOVA/Student's t test. Physical hypoxia increased expression of both CD11b and CD18 over time and augmented their LPS-induced up-regulation. Isolated chemical hypoxia did not change neutrophil expression of CD11b or CD18, but partially inhibited neutrophil CD11b and CD18 up-regulation by LPS. LPS-induced TNFR down-regulation was not affected by physical hypoxia, which failed to alter TNFR expression in this model.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hypoxia-induced alterations of neutrophil membrane receptors. 763 Jan 18

The study deals with an animal model for the problems of surgical intensive care patients. Following repeated applications of E. coli endotoxin WO 111:B4 under standard conditions, specific hemodynamic and biochemical (TNF, TXA2, PGI2, IL-6, PAF) and morphological (endothelium of the lung) alterations were detected. ARDS patterns induced by the sepsis were analyzed by high-frequency measurement of pressure and flow (385 measurements per breathing cycle). The role of the intestine in sepsis was investigated by ion-selective monitoring of surface potassium activity comparing mucosa and serosa. Every injection of endotoxin was followed by a selective increase of the potassium activity revealing relative ischemia induced by the endotoxin. The profile of the potassium levels on the surface correlates both with the cardiac output and with the prostacyclin levels. The continuous narrowing of the difference between mucosa and serosa, potassium during the period of investigation can be regarded as evidence for pathologic change in permeability fostering the septic course.
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PMID:[Septic shock and multiple organ failure in surgical intensive care. An animal experiment model on the analysis of pulmonary and intestinal dysfunction]. 769 Jan 6

At physiological and pharmacological doses, adenosine protects tissues against a varieties of injuries: ischemia-reperfusion, convulsions, inflammation.... We tested the hypothesis that the antiinflammatory properties of adenosine occur via a down-regulation of TNF. Agonists of adenosine receptors (ARA) and agents potentiating endogenous adenosine (APA) were evaluated for their effects on TNF production by endotoxin-stimulated human monocytes. Additionally, one of the most potent agonists, R-phenylisopropyladenosine (R-PIA), was tested on two experimental models of acute phase response, endotoxin shock and carrageenan-induced plantar oedema. Several ARA and APA inhibited monocyte TNF production in a concentration-dependent manner. R-PIA and other ARA were active at micromolar concentrations. The property is pharmacologically relevant since rats receiving a lethal dose of endotoxins were protected by R-PIA and endotoxin-induced serum TNF levels were abolished by a pretreatment with R-PIA. Inhibitory effects on serum TNF production were obtained with similar doses of dexamethasone sodium phosphate and one hundred-fold higher doses of pentoxifylline. R-PIA was also found active on carrageenan-induced oedema. The anti-oedematous properties of R-PIA were associated with a marked reduction of locally-produced TNF and were also observed after the administration of dexamethasone, pentoxifylline and a neutralizing anti-TNF antibody. Our results indicate that adenosine is a potent inhibitor of TNF production induced by different stimuli. This property could lead to therapeutic applications in inflammatory diseases and other in which TNF is known to play a pathogenic or aggravating role. Comparison between ARA and APA in terms of tolerance and efficacy merits further attention.
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PMID:[Activity of adenosine in relation to tumor necrosis factor (TNF). Therapeutic outlook]. 778 49

The liver is highly susceptible to a number of pathological insults, including ischemia/reperfusion injury. One of the striking consequences of liver injury is the associated pulmonary dysfunction that may be related to the release of hepatic-derived cytokines. We have previously employed an animal model of hepatic ischemia/reperfusion injury, and demonstrated that this injury causes the production and release of hepatic-derived TNF, which mediates a neutrophil-dependent pulmonary microvascular injury. In this study, we have extended these previous observations to assess whether an interrelationship between TNF and the neutrophil chemoattractant/activating factor, epithelial neutrophil activating protein-78 (ENA-78), exists that may be accountable for the pathology of lung injury found in this model. In the context of hepatic ischemia/reperfusion injury, we demonstrated the following alterations in lung pathophysiology: (a) an increase in pulmonary microvascular permeability, lung neutrophil sequestration, and production of pulmonary-derived ENA-78; (b) passive immunization with neutralizing TNF antiserum resulted in a significant suppression of pulmonary-derived ENA-78; and (c) passive immunization with neutralizing ENA-78 antiserum resulted in a significant attenuation of pulmonary neutrophil sequestration and microvascular permeability similar to our previous studies with anti-TNF. These findings support the notion that pulmonary ENA-78 produced in response to hepatic-derived TNF is an important mediator of lung injury.
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PMID:Chemokine expression during hepatic ischemia/reperfusion-induced lung injury in the rat. The role of epithelial neutrophil activating protein. 781 7

Monoclonal antibody to tumor necrosis factor-alpha (TNFa-MAb), z8, was used to explore protective effect on multiple organ dysfunction caused by intestinal ischemia and reperfusion in rats. Systemic plasma TNF level rose rapidly after release of the clamp, on superior mesenteric artery, and reached peak level 2 hours later. Endotoxemia and bacteremia were associated with systemic TNF level, and portal endotoxin concentration increased significantly before elevation of TNF activity. Pretreatment with anti-TNFa antibody markedly attenuated the increase of TNF level and provided protection from the development of hypotension, vital organ dysfunction, and metabolic acidosis. As a result the survival rate in treatment group increased by 35.7%. Our results demonstrated that TNF might play an important role in mediating the pathophysiologic changes in the pathogenesis of multiple organ damage in this intestinal ischemia-reperfusion injury model, and monoclonal antibody to TNF offered significant protection against multiple organ dysfunction or failure after severe trauma.
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PMID:[Protective effect of monoclonal antibody of tumor necrosis factor-alpha for vital organs in a model suffering from intestinal ischemia and reperfusion injury]. 811 80

Ischemia followed by reperfusion of the rat hind limb resulted in local evidence of injury, as reflected in increased vascular permeability and hemorrhage in skeletal muscle as well as distant organ injury, as reflected by increased vascular permeability and hemorrhage in lung. These changes were proportional to the duration of reperfusion and were associated with neutrophil accumulation in tissue, as quantitated by myeloperoxidase (MPO) content. There was corresponding evidence of complement depletion and increases in plasma IL-1 and IL-6. On the basis of interventional approaches, limb and lung vascular injury was neutrophil and complement dependent and was attenuated by treatment with antioxidants. Products of L-arginine were involved in the development of vascular injury since antagonists of L-arginine were protective. Based on the use of blocking antibodies, the cytokines TNF alpha and IL-1 were also involved in the development of tissue injury. Finally, both LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) beta 2 integrins were required as well as the endothelial adhesion molecules E-selectin and ICAM-1. Protective interventions were more protective that both local and remote organ injury following ischemia-reperfusion is in lung than in skeletal muscle. There were, in general, parallel effects when tissue protection was related to reduction in MPO content. These data suggest dependent on toxic oxygen and L-arginine products of neutrophils, the accumulation of which can be linked to cytokines (TNF alpha, IL-1), beta 2 integrins and endothelial adhesion molecules.
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PMID:Ischemia-reperfusion injury. 831 38

Recent studies suggest that graft microvascular endothelia may play an important role in the regulation of rejection. Alloantigen-dependent changes in microvascular endothelial phenotype may be associated with differences in infiltrate function in allografts vs. isografts, as reflected in alloantigen-specific CTL accumulation and cytokine production. To correlate cytokine production with differences in microvascular endothelial phenotype during allograft inflammation, we used PCR to identify cytokine mRNAs isolated from pooled cardiac isografts and allografts on days 1, 3, and 5 after transplantation. Graft microvascular endothelia express an inflamed phenotype associated with wound healing and the repair of tissue damage due to mechanical trauma, ischemia, and/or reperfusion injury--i.e., high levels of ICAM-1 expression and MECA-32 mAb reactivity. By day 1 in both isografts and allografts, mRNAs for the cytokines IL1 alpha, IL6, TNF, LT, and TGF beta are upregulated or induced. By the third day in cardiac allografts, an antigen-dependent endothelial phenotype is expressed, characterized by the presence of cell surface VCAM-1. Concomitantly, mRNAs for the lymphokines IL2 and IFN gamma are detected, followed by IL4 mRNA by day 5. The expression of VCAM-1 by allograft endothelia may influence the inflammatory process, by physically recruiting specific T cell subpopulations into the response and/or by delivering additional signals to the infiltrating cells. Eventually, these and other regulatory events occurring at these early times initiate a process that later results in alloreactive tissue destruction.
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PMID:Alloantigen-dependent endothelial phenotype and lymphokine mRNA expression in rejecting murine cardiac allografts. 847 68

Endothelial dysfunction is an important early-recurring phenomenon in virtually all forms of ischemia-reperfusion, including a variety of circulatory shock states. The dysfunction appears to be triggered within 2.5 min of the endothelial generation of a large burst of superoxide radicals. However, the initial dysfunction may be amplified by neutrophil-generated factors including oxygen-derived free radicals, cytokines, proteases, and lipid mediators. Moreover, adhesive molecules on the surface of the PMN, along with their ligands on the endothelial cell membrane, appear to promote endothelial dysfunction in ways that may go beyond the adherence of neutrophils on the endothelial surface. These interactions remain to be elucidated but may involve intricate cell signaling pathways. A variety of pharmacologic agents exert endothelial protective effects in ischemia-reperfusion and circulatory shock states. Table 1 summarizes these agents and indicates the major mechanism of preservation of the endothelium. These substances can be classified into three broad categories: (a) substances replacing endogenous cytoprotective agents of endothelial origin including prostacyclin (PGI2), endothelium-derived relaxing factor (EDRF), and adenosine: the endothelium protecting agents include these substances as well as stable analogs of PGI2, and nitric oxide donors; (b) substances that inhibit pro-inflammatory mediators of endothelial origin: the pro-inflammatory agents are primarily platelet activating factor (PAF) and oxygen-derived free radicals (e.g. superoxide radicals) although other mediators may be involved. The therapeutic agents useful in this area are PAF receptor antagonists and free radical scavengers (e.g. superoxide dismutase); (c) substances that inhibit neutrophils or neutrophil-derived mediators: the major neutrophil-derived mediators are oxygen-derived free radicals, cytokines (e.g. TNF alpha and IL-1 beta), proteases (e.g. elastase), and lipid mediators (e.g. LTB4). In addition, adhesive molecules on the neutrophil surface and their endothelial ligands promote endothelial dysfunction and the action of adherent neutrophils. Agents that inhibit some of these mediators are transforming growth factor-beta (TGF-beta), elastase inhibitors, leukotriene B4 (LTB4) receptor antagonists and monoclonal antibodies to adhesive proteins (e.g. anti-CD18, anti-ICAM-1). Further work is needed to clarify these findings and to determine the physiologic and pathophysiologic interactions among these diverse agents. This topic of endothelial dysfunction represents a fertile area for further investigation to elucidate the complex mechanisms of neutrophil-endothelial interactions. These interactions lead to neutrophil adherence to the endothelium, neutrophil migration into the underlying tissues, and subsequent tissue injury (e.g. myocardial reperfusion injury).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacology of the endothelium in ischemia-reperfusion and circulatory shock. 849 55


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