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)

Tumor necrosis factor (TNF)-alpha has significant biologic actions in many circumstances, such as infectious diseases, ischemia/reperfusion injury, and delayed-type hypersensitivity reactions. Based on the hypothesis that manipulation of TNF can play an important role in treatment of heart transplant rejection, the objective of this study was to determine whether anti-TNF antibodies could prolong cardiac allograft survival. Hearts from brown rats were transplanted to the necks of recipient Lewis rats. Graft survival was determined by direct palpation of the heart; complete graft rejection was defined by cessation of contraction. In untreated rats, the hearts were rejected 6.8 +/- 0.6 days (n = 10; mean +/- SEM) after transplantation. The mononuclear cell infiltrate in the transplanted hearts stained intensely for TNF by immunohistochemistry, indicating that TNF was present within the inflammatory cells associated with the rejection process. In rats receiving a single injection of anti-TNF antibody at the time of transplantation (n = 6), however, graft survival was nearly doubled (12.7 +/- 1.4 days; p less than 0.001 vs controls). Prolonged cardiac graft survival was also evident if the anti-TNF treatment was delayed until 1 day (n = 5; rejection at 16.2 +/- 2.4 days; p less than 0.001 vs controls) or even 3 days after transplantation (n = 5; rejection at 11.4 +/- 2.3 days; p less than 0.005 vs controls). Treatment at 5 days after transplantation, however, was not effective (n = 3; rejection at 7.7 +/- 0.6 days; p, not significant vs controls). The data indicate that a single bolus of anti-TNF antibodies can delay heart transplant rejection, even when administered up to 3 days after implantation, supporting the potential utility of anti-TNF therapy for treatment of heart transplant rejection.
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PMID:Antibodies against tumor necrosis factor prolong cardiac allograft survival in the rat. 157 39

Endotoxemia remains the leading cause of death in horses, being intimately involved in the pathogenesis of gastrointestinal disorders that cause colic and neonatal foal septicemia. Endotoxins, normally present within the bowel, gain access to the blood across damaged intestinal mucosa, or endotoxemia occurs when gram negative organisms proliferate in tissues. Endotoxins are removed from the circulation by the mononuclear phagocyte system, and the response of mononuclear phagocytes to these lipopolysaccharides (LPS) play an important role in determining the severity of clinical disease. Macrophages become highly activated for enhanced secretory, phagocytic and cidal functions by LPS. Macrophage-derived cytokines are responsible for many of the pathophysiologic consequences of endotoxemia. The arachidonic acid metabolites, prostacyclin and thromboxane A2 likely mediate early hemodynamic dysfunction and the leukotrienes may potentiate tissue ischemia during endotoxemia. Interleukin 1 (IL-1) induces fever and is responsible for the inflammatory cascade, which constitutes the acute phase response. Tumor necrosis factor (TNF), an important proximal mediator of the effects of LPS, acts to initiate events and formation of other molecules that affect shock and tissue injury. Systemic administration of TNF produces most of the physiologic derangements that are associated with endotoxemia and antibodies that are directed against TNF significantly reduce LPS-induced mortality in experimental animals. In response to endotoxins, mononuclear phagocytes express thromboplastin-like procoagulant activity (PCA), which initiates microvascular thrombosis. Both IL-1 and TNF induce PCA expression, creating a positive feedback loop for LPS-induced coagulopathy. A macrophage-derived platelet activating factor contributes to coagulation dysfunction and further stimulates arachidonic acid metabolism. The ultimate consequences of endotoxemia are multiple system organ failure and death. The numerous feedback loops and intertwining cascades of mediators during endotoxemia defy simplistic methods of treatment. The optimal therapy likely involves methods to alter the generation of inflammatory mediators by mononuclear phagocytes.
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PMID:Endotoxemia in horses. A review of cellular and humoral mediators involved in its pathogenesis. 192 Feb 54

Tumor necrosis factor (TNF) facilitates superoxide production, and spin traps may detoxify superoxide by acting as superoxide dismutase mimics. We investigated the ability of a stable nitroxide spin trap, TEMPOL, to protect TNF-sensitive cells from exogenously added TNF. WEHI or L929 cells were incubated with TNF (500 units/ml) for 18 hr either simultaneously with 0 to 8 mM TEMPOL or with the TEMPOL added at varying intervals after TNF exposure. A dose-dependent increase in survival was noted in the TEMPOL-treated cells, with 92 +/- 2% survival of WEHIs treated with 4 mM TEMPOL compared to 26 +/- 1% survival for non-TEMPOL-exposed cells (P2 less than 0.01). Significant increases in survival could be accomplished with as late as 15-hr delayed addition of the compound. The mechanism of protection does not seem to involve newly synthesized protein, and Northern blot analysis revealed that TEMPOL does not induce the genes for MnSOD or Cu-ZnSOD. The ability of TEMPOL to protect against TNF injury, even when exposure is delayed, may prove useful in conditions thought to be associated with free radical-lymphokine interactions such as ischemia-reperfusion, oxygen toxicity, or sepsis.
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PMID:Spin trap protection from tumor necrosis factor cytotoxicity. 203 86

A complex interplay of peptides known as the cytokines may have a tremendous influence over a number of inflammatory related conditions. Tumor necrosis factor occupies an early and central role in the initiation of cascades that ultimately influences a number of cell types involved in tissue inflammation, tissue rejection, cancer, and injuries from ischemia reperfusion. Only now are the cascades being defined and therapies being designed to interrupt the toxic effects of these cytokines and to treat malignancy.
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PMID:The macrophage, TNF, and other cytokines. 753 21

Twenty-four horses were randomly allocated to 3 groups. Horses were anesthetized, subjected to a ventral midline celiotomy, and the large colon was exteriorized and instrumented. Group-1 horses served as sham-operated controls. Group-2 horses were subjected to 6 hours of low-flow colonic arterial ischemia, and group-3 horses were subjected to 3 hours of ischemia and 3 hours of reperfusion. Baseline (BL) samples were collected, then low-flow ischemia was induced by reducing ventral colonic arterial blood flow to 20% of BL. All horses were monitored for 6 hours after BL data were collected. Blood samples were collected from the colonic vein and main pulmonary artery (systemic venous [SV]) for measurement of plasma endotoxin, 6-keto prostaglandin F1 alpha (6-kPG), thromboxane B2 (TXB2), and prostaglandin E2 (PGE2) concentrations. Tumor necrosis factor and interleukin-6 activities were measured in colonic venous (CV) serum samples. Data were analyzed, using two-way ANOVA, and post-hoc comparisons were made, using Dunnett's and Tukey's tests. Statistical significance was set at P < 0.05. Endotoxin was not detected in CV or SV plasma at any time. There was no detectable tumor necrosis factor or interleukin-6 activity in CV samples at any time. There were no differences at BL among groups for CV or SV 6-kPG, PGE2, or TXB2 concentrations, nor were there any changes across time in group-1 horses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Systemic and colonic venous plasma eicosanoid and endotoxin concentrations, and colonic venous serum tumor necrosis factor and interleukin-6 activities in horses during low-flow ischemia and reperfusion of the large colon. 766 63

Tumor necrosis factor-alpha (TNF-alpha) has been implicated in several late consequences of trauma such as sepsis, multiple organ failure, and ischemia-reperfusion injury. However, no data are available to indicate whether TNF-alpha is involved in the initial pathophysiologic response to trauma. To address this issue, serum TNF-alpha was determined (by ELISA) longitudinally (first blood sample on admission) in 100 randomly selected trauma patients admitted to the emergency department and trauma division at Jefferson Medical Center, Philadelphia. The TNF-alpha levels were detectable at one or more time points in 35 patients. Mean values tended to be elevated (50.3 +/- 11.5 pg/mL) during the first 5 days, but this trend did not differ statistically from that in healthy controls (n = 12) and did not correlate with the severity of injury (Injury Severity Score and Glasgow Coma Scale score). The TNF-alpha response was not dependent on the mechanism and site of injury, the presence of shock (systolic blood pressure < 90 mm Hg), and the need for emergent surgery. Also, serum TNF-alpha levels were not significantly elevated in patients who subsequently developed multiple organ failure (n = 4), septic shock (n = 5), or both (n = 3). Taken together, these data do not support a role for circulating TNF-alpha in the initial acute inflammatory response to trauma.
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PMID:Serum tumor necrosis factor-alpha profile in trauma patients. 823 Mar 32

Cardiac surgery with cardiopulmonary bypass triggers an inflammatory response involving proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, and interleukin-8. To elucidate the pathophysiology of this cytokine response, we explored the possible differences in cytokine responses between patients undergoing heart transplantation and those undergoing coronary artery bypass grafting. Plasma levels of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured in eight patients undergoing heart transplantation (mean age 44 years) and eight patients undergoing coronary artery bypass grafting (mean age 61 years). Duration of cardiopulmonary bypass and ischemic time were both longer in the heart transplantation group than in the coronary artery bypass grafting group (133 +/- 26 min vs 100 +/- 31 min, p < 0.05, and 130 +/- 47 min vs 58 +/- 21 min, p < 0.005, respectively). Samples were collected before heparin administration, at aortic crossclamping and declamping, and at 0.5, 1, 1.5, 2, 4, 12, and 24 hours after declamping. Tumor necrosis factor-alpha levels were significantly higher 30 minutes after aortic declamping in the heart transplantation group than in the coronary artery bypass grafting group (68 +/- 30 vs 18 +/- 5 pg/ml, p < 0.05). Interleukin-6 and interleukin-8 levels were also significantly higher 90 minutes after declamping in patients undergoing heart transplantation than in those undergoing coronary artery bypass grafting (310 +/- 63 vs 169 +/- 24 pg/ml, p < 0.05, and 73 +/- 17 vs 24 +/- 5 pg/ml, p < 0.01, respectively). Furthermore, interleukin-6 and interleukin-8 values 90 minutes after declamping were significantly correlated with the ischemic time (r = 0.72 and r = 0.82, respectively, both p < 0.05). Interleukin-10 levels in both groups rose to reach a peak value of around 115 pg/ml 1 hour after declamping. Patients undergoing heart transplantation exhibited a second peak of tumor necrosis factor-alpha, interleukin-8, and interleukin-10 levels 12 hours after declamping, probably related to the administration of rabbit antihuman thymocyte immunoglobulin (Thymoglobuline) 3 hours after declamping. Interleukin-6 levels decreased more significantly 12 and 24 hours after declamping in patients undergoing heart transplantation, probably related to methylprednisolone therapy. In conclusion, cardiopulmonary bypass is associated with the production of both proinflammatory and antiinflammatory cytokines. The production of proinflammatory cytokines in patients undergoing heart transplantation is higher than that in patients undergoing coronary artery bypass grafting, and this increase could be related to the longer duration of ischemia in the former group. The later course of cytokine levels after heart transplantation may be further influenced by immunosuppressive therapy.
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PMID:Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. 875 37

Neutrophil adhesion to the vascular endothelium is enhanced during tissue ischemia and/or inflammation, conditions that are associated with tissue acidosis. This study examined the effects of hypercarbic acidosis (10 or 20% CO2) and of hypocarbic alkalosis (0% CO2) on human neutrophil CD18 and human aortic endothelial cell intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin expression quantified by flow cytometry. Acidosis with 20% CO2 for 4 h decreased ICAM-1 to 60.6 +/- 9.7% of control. In contrast, alkalosis with 0% CO2 for 4 h enhanced ICAM-1 expression to 143.8 +/- 10.1% of control. There was no pH dependence of VCAM-1 or E-selectin expression. Tumor necrosis factor-alpha (TNF-alpha; 10 ng/ml) increased endothelial ICAM-1, E-selectin, and VCAM-1; under these conditions, acidosis with 20% CO2 blunted both ICAM-1 and E-selectin surface expression compared with 5% CO2-, TNF-alpha-treated cells. Hypercarbic acidosis with 20% CO2 increased neutrophil CD18 expression and enhanced neutrophil adhesion. This latter effect was inhibited by neutrophil pretreatment with an anti-CD18 monoclonal antibody. In contrast, when only endothelial cells were preincubated with the hypercarbic buffer, neutrophil adhesion diminished to 55.6 +/- 7.8% of control. The results suggest that acidosis generated during tissue ischemia/inflammation may induce CD18-mediated neutrophil adhesion despite a decrease in ICAM-1 expression.
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PMID:pH dependence of neutrophil-endothelial cell adhesion and adhesion molecule expression. 884 27

Tumor necrosis factor (TNF) gene expression in rat retina following transient ischemia was studied by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Gene expression for other cytokines was also studied by RT-PCR. Although very little expression for TNF gene was detected in normal retina, it was markedly increased 0.5-48 h after reperfusion, with peak expression at 12 h (20-fold of control). Gene expression for interleukin-6, interferon-gamma, and transforming growth factor-beta 1 was also increased. The results provide evidence that retinal ischemia can up-regulate cytokine gene expression in the retina.
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PMID:Increased cytokine gene expression in rat retina following transient ischemia. 887 88

Cytokines are recognized to play an important role in acute stroke. Tumor necrosis factor-alpha (TNF) is one of the pro-inflammatory cytokines and is expressed in ischemic brain. We hypothesized that TNF might play a role in the regulation of tolerance to ischemia when administered prior to the ischemic episode. We studied the effects of pretreatment of TNF administered intravenously, intraperitoneally, or intracisternally in mice that were subjected to middle cerebral artery occlusion (MCAO) 48 h later. MCAO was performed in BALB/C mice by direct cauterization of distal MCA, which resulted in pure cortical infarction. A significant reduction in infarct size was noted in mice pretreated by TNF at the dose of 0.5 microgram/mouse (p < 0.01) intracisternally. At the doses used in this study, administration of TNF by intravenous or intraperitoneal routes was not effective. Immunohistochemical analysis of brains subjected to 24 h of MCAO revealed a significant decrease in CD11b immunoreactivity after TNF pretreatment compared with control MCAO. Preconditioning with TNF affects infarct size in a time- and dose-dependent manner. TNF induces significant protection against ischemic brain injury and is likely to be involved in the signaling pathways that regulate ischemic tolerance.
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PMID:TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice. 918 85


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