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)

Although there is much evidence to substantiate the view that tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of multiple organ injury subsequent to intestinal ischemia/reperfusion (I/R), it is still unclear whether TNF is involved in triggering the release of other inflammatory mediators in this condition. The current study was designed to determine the potential effects of TNF blockade, by means of monoclonal antibody (TNF MoAb) treatment, on plasma interleukin 6 (IL-6) in rats after acute intestinal I/R injury. Anesthetized rats underwent 75-min occlusion of superior mesenteric artery followed by 6 hr of reperfusion. The animals were treated with TNF MoAb or control protein at a dose of 20 mg/kg i.v. 30 min before the onset of I/R. Similar IL-6 responses in both the portal and the systemic circulation were observed in animals subjected to intestinal I/R, who showed a progressive increase in plasma IL-6 concentration upon release of the clamp. In animals receiving TNF MoAb before I/R, the subsequent IL-6 release following reperfusion was significantly blunted compared to the levels in controls (P < 0.05). The present study demonstrates that the activation and/or release of IL-6 in the setting of acute gut I/R may, at least in part, be mediated via TNF-dependent mechanisms, providing further evidence that a complex interaction exists between TNF and IL-6.
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PMID:IL-6 release after intestinal ischemia/reperfusion in rats is under partial control of TNF. 922 22

Subarachnoid hemorrhage (SAH) causes an inflammatory reaction and may lead to ischemic brain damage. Experimental ischemia has been shown to be connected with the alarm-reaction cytokines interleukin-1 receptor antagonist (IL-1Ra) and tumor necrosis factor-alpha (TNF alpha). Increased levels of these cytokines, however, have not been detected thus far in patients following an SAH event. For this reason daily cerebrospinal fluid (CSF) samples were collected from 22 consecutively enrolled patients with SAH and from 10 non-SAH patients (controls). The CSF samples were studied using immunoassays for IL-1Ra and TNF alpha to investigate whether an SAH caused increased cytokine levels. The mean IL-1Ra levels were significantly higher in patients with SAH who were in poor clinical condition on admission than in those who were in good condition (318 pg/ml vs. 82 pg/ml, p < 0.02). The IL-1Ra levels increased during delayed ischemic episodes and after surgery in patients who were in poor clinical condition. Significant increases in IL-1Ra and TNF alpha were detected during Days 4 through 10 in patients suffering from SAH who eventually had a poor outcome (p < 0.05). Patients with good outcomes and control patients had low levels of these cytokines. The levels of IL-1Ra increased after surgery in patients with Hunt and Hess Grades III through V, but not in those with Grade I or II. This finding indicates that patients in poor clinical condition have a labile biochemical state in the brain that is reflected in increased cytokine levels following the surgical trauma. Both IL-1Ra and TNF alpha are known to induce fever, malaise, leukocytosis, and nitric oxide synthesis and to mediate ischemic and traumatic brain injuries. The present study shows that levels of these cytokines increase after SAH occurs and that high cytokine levels correlate with brain damage. It is therefore likely that fever, leukocytosis, and nitric oxide synthesis are also mediated by IL-1 in patients suffering from SAH and it is probable that the inflammatory mediators contribute to brain damage.
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PMID:Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor-alpha following subarachnoid hemorrhage. 925 84

A method to reduce ischemia-reperfusion (I/R) injury can be an important criterion to improve the preservation solution. Although University of Wisconsin solution (UW) works as a lung preservation solution, its attenuation effect on I/R injury has not been investigated. We attempted to determine whether, by adding various protective agents, modified UW solutions will enhance the I/R attenuation by UW. We examined the I/R injury in an isolated rat lung model. Various solutions, e.g., physiological salt solution (PSS), UW, and modified UW solutions containing various protective agents such as prostaglandin E1, dexamethasone, U-74389G, or dibutyryl adenosine 3',5'-cyclic monophosphate were perfused individually to evaluate the I/R injury. Isolated rat lung experiments, with ischemia for 45 min, then reperfusion for 60 min, were conducted in a closed circulating system. Hemodynamic changes, lung weight gain (LWG), capillary filtration coefficient (Kfc), protein content of lavage fluid, concentration of cytokines, and lung histopathology were analyzed. Results showed that the acute I/R lung injury with immediate permeability pulmonary edema was associated with an increase in tumor necrosis factor-alpha (TNF-alpha) production. A significant correlation existed between TNF-alpha and Kfc (r = 0.8, P < 0.0001) and TNF-alpha and LWG (r = 0. 9, P < 0.0001), indicating that TNF-alpha is an important cytokine modulating early I/R injury. Significantly lower levels of Kfc, LWG, TNF-alpha, and protein concentration of lung lavage (P < 0.05) were found in the UW-perfused group than in the control group perfused with PSS. Modified UW promoted the protective effect of UW to further decrease Kfc, LWG, and TNF-alpha (P < 0.05). Histopathological observations also substantiated this evidence. In the UW+U-74389G group, bronchial alveolar lavage fluid contained lowest protein concentration. We conclude that the UW solution attenuates I/R injury of rat lung and that the modified UW solutions further enhance the effect of UW in reducing I/R injury. Among modified solutions, UW+U-74389G is the best. Further investigation of the improved effects of the modified UW solutions would be beneficial in lung transplantation.
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PMID:PGE1, dexamethasone, U-74389G, or Bt2-cAMP as an additive to promote protection by UW solution in I/R injury. 926 56

The intestine plays a major role in the pathophysiology of multiorgan failure. Although the systemic inflammatory response might be induced by endotoxin released through bacterial translocation, other factors such as intestinal ischemia might be implicated. We investigated the relationship between intestinal ischemia-reperfusion and cytokine release in rat models of hemorrhagic or endotoxic shock. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), lactate, and endotoxin, as well as macrophage TNF-alpha and IL-6 mRNA expression, were assessed at the end of shock and resuscitation. Hemodynamic changes and lactate levels suggested the presence of intestinal ischemia in both models. Mesenteric levels of TNF-alpha and IL-6 were increased by hemorrhage and further increased after saline resuscitation. Similar results were obtained with mRNA cytokine gene expression in macrophages. Endotoxin was not detectable in the hemorrhagic group. Endotoxic shock also increased production of cytokines, which, in contrast to hemorrhage, was not further increased by resuscitation. These results suggest that intestinal ischemia-reperfusion upon hemorrhage and resuscitation may be a major trigger for cytokine gene expression in the absence of endotoxin.
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PMID:Gut ischemia and mesenteric synthesis of inflammatory cytokines after hemorrhagic or endotoxic shock. 927 9

Phospholipase A2 has been considered to play a role in physiological membrane turnover in cardiac tissue and in the degradation of membrane lipids under pathophysiological conditions, such as ischemia and reperfusion. We report the cloning of a cDNA encoding a member of the Ca2+-dependent, low molecular mass phospholipase A2 (PLA2) present in rat heart. The cDNA predicts a mature protein of 146 amino acid residues including a 21 amino acid sequence at the N-terminal end, which has the features characteristic of eukaryotic secretory signal peptides. The deduced amino acid sequence constitutes an enzyme of the group II class of PLA2s, and resembles PLA2s from other mammalian sources. A Northern blot analysis performed to determine the tissue distribution showed that rat ileum contains the largest amount of the PLA2 transcript among the tissues examined, a weaker signal was present in heart, spleen and soleus muscle, and no signal could be detected in EDL muscle, stomach, liver, kidney, brain and lung. Northern blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) techniques indicate the presence of this enzyme in neonatal and adult rat cardiomyocytes and in a cultured rat cardiac fibroblast-like cell line, but not in rat cardiac-derived endothelial cell lines. Transcription levels of rat heart group II PLA2 in isolated neonatal rat cardiomyocytes were found to increase after stimulating the cells with tumor necrosis factor-alpha (TNF-alpha) or the alpha1-adrenergic agonist phenylephrine.
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PMID:Cloning and cellular distribution of a group II phospholipase A2 expressed in the heart. 928 42

Inhibition of nitric oxide (NO) synthesis in mesenteric microvessels increases leukocyte rolling. The objective of this study was to determine whether inducible NO synthase (iNOS) can modulate tumor necrosis factor-alpha (TNF-alpha)-induced leukocyte rolling. Leukocyte rolling was examined using intravital microscopy of TNF-alpha-treated feline mesenteric microvasculature. Leukocyte rolling increased progressively over 3 h of TNF-alpha treatment. Pretreatment with the selective iNOS inhibitor aminoguanidine further doubled TNF-alpha-induced leukocyte rolling. Aminoguanidine alone did not affect baseline blood pressure or leukocyte kinetics. However, in the same animals NG-nitro-L-arginine methyl ester caused a rapid increase in blood pressure, confirming that constitutive NOS activity persisted in aminoguanidine-treated animals. Furthermore, aminoguanidine did not affect leukocyte rolling in an acute model of leukocyte recruitment (ischemia/reperfusion), suggesting that the exacerbated rolling induced by aminoguanidine with TNF-alpha as a stimulus was not a nonspecific effect. Addition of the NO donor spermine-NO had no effect on TNF-alpha-associated leukocyte rolling. These data raise the possibility of a physiological role for the increased production of NO from iNOS, i.e., regulation of leukocyte rolling and potentially the inflammatory response.
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PMID:Endogenous but not exogenous nitric oxide decreases TNF-alpha-induced leukocyte rolling. 931 65

Donor pretreatment is a new concept in organ preservation. Pentoxifylline (PTX) has been reported to suppress the activation of Kupffer cells and to decrease injury to the hepatic graft after rat liver transplantation. We evaluated the efficiency of PTX pretreatment on the donor against hepatic injury following cold ischemia (CI) or warm ischemia (WI) using the rat liver transplantation model. Dose dependency: every rat was injected intraperitoneally with PTX (30, 50, or 80 mg/kg) or saline. One hour later, the portal vein (PV) and the hepatic artery (HA) were clamped for 30 min. Transplantation: the donor rat was injected intraperitoneally with 50 mg/kg PTX or saline, 1 hr before laparotomy. Animals were divided into two groups. In the CI group, grafts were preserved for 12 hr in University of Wisconsin solution at 4 degrees C and transplanted. In the WI group, the PV and the HA in the donor were clamped for 30 min before donor surgery, and the grafts were transplanted. Serum levels of tumor necrosis factor-alpha (TNF-alpha), glutathione S-transferase-alpha (GST-alpha), and aspartate transaminase (AST) were measured at 30 min, 3 hr, and 24 hr after reperfusion of the PV. Compared with those of a control group, the serum levels of TNF-alpha, GST-alpha, and AST in the PTX-pretreated groups were significantly lower after both CI and WI at 30 min and further suppressed in the WI group at 24 hr. These results indicate that PTX pretreatment on the donor is effective for suppression of hepatic injury after both CI and WI.
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PMID:Efficiency of pentoxifylline in donor pretreatment in rat liver transplantation. 935 39

Two contrasting roles, one beneficial and the injurious, have been proposed for tumor necrosis factor (TNF) in the pathogenesis of cerebral ischemia. Reported here are results obtained in a standard model of permanent focal cortical ischemia in rats, in which the volume of cerebral infarction is measured after permanent occlusion of the middle cerebral artery. Administration of neutralizing anti-rat TNF antibodies (P114) into the brain cortex significantly reduced ischemic brain damage (85% reduced infarct volume as compared with preimmune-treated controls). Similar results were achieved by systemic administration of CNI-1493, a recently described tetravalent guanylhydrazone compound, which effectively inhibited endogenous brain TNF synthesis and conferred significant protection against the development of cerebral infarction (80% reduced infarct volume as compared with vehicle controls treated 1 h postischemia with 10 mg/kg). P114 anti-TNF and CNI-1493 were each cerebroprotective when given within a clinically relevant time window for up to 2 h after the onset of ischemia. These findings establish an important, pathophysiological role of TNF in mediating the progression of ischemic brain damage, and suggest that inhibiting TNF with CNI-1493 may be beneficial in the future treatment of stroke.
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PMID:Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia. 936 44

Lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-alpha independently induce cardioprotection against ischemia in the rat at 24 h after administration, suggesting that endogenously synthesized TNF-alpha may play a role in LPS-induced protection. The purposes of this study were 1) to delineate the time course of LPS-induced cardiac functional protection against ischemia and its relation with myocardial and circulating TNF-alpha profile, 2) to examine whether prior protein synthesis inhibition abrogates the protection, and 3) to assess the effects of TNF-alpha inhibition and neutralization on the protection. Rats were treated with LPS (0.5 mg/kg i.p.). Cardiac functional resistance to normothermic global ischemia-reperfusion was examined at sequential time points after LPS treatment in isolated hearts by the Langendorff technique. Myocardial and circulating TNF-alpha was determined by enzyme-linked immunosorbent assay at 1-24 h after LPS treatment. Protection was apparent at 24 h, 3 days, and 7 days but not at 2 or 12 h. Maximal protection at 3 days was abolished by cycloheximide pretreatment (0.5 mg/kg i.p. 3 h before LPS treatment). Increases in myocardial and circulating TNF-alpha preceded the acquisition of protection. Dexamethasone pretreatment (4.0 or 8.0 mg/kg i.p. 30 min before LPS treatment) abolished peak increase in myocardial TNF-alpha and substantially suppressed circulating TNF-alpha (54.3 and 85.9% inhibition, respectively) without an influence on the maximal protection. Similarly, maximal protection was not affected by TNF binding protein (40 or 80 microg/kg i.v. immediately after LPS treatment). The results suggest that LPS-induced cardiac functional protection against ischemia is a delayed and long-lasting protective response that may involve de novo protein synthesis. Although LPS-induced increase in myocardial and circulating TNF-alpha precedes the delayed protection, it may not be required for the delayed protection.
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PMID:LPS induces late cardiac functional protection against ischemia independent of cardiac and circulating TNF-alpha. 936 58

Kupffer cells (KCs) have been implicated in the leukocyte recruitment and microvascular dysfunction associated with liver inflammation. The overall objective of this study was to assess the role of KCs in the leukocyte adhesion and oxidative stress elicited in the liver by gut ischemia/reperfusion (I/R). The accumulation of rhodamine-6G-labeled leukocytes and the number of nonperfused sinusoids (NPS) were monitored (by intravital microscopy) in mouse liver for 1 hour after a 15-minute period of normothermic intestinal ischemia. Autofluorescence of pyridine nucleotide [NAD(P)H] was measured as an index of mitochondrial O2 consumption and redox status. Leukostasis, as well as increases in NPS and NAD(P)H autofluorescence (indicating hypoxia), were observed in the liver at 60 minutes after gut I/R. Pretreatment with gadolinium chloride (GdCl3), which reduces KC function, attenuated the liver leukostasis and NPS elicited by gut I/R. The platelet activating factor (PAF) antagonist, WEB2086, and a tumor necrosis factor (TNF)-alpha-specific antibody were also effective in attenuating the gut I/R-induced leukostasis and NAD(P)H autofluorescence. The findings of this study suggest that KCs play an important role in mediating the leukocyte recruitment, impaired sinusoidal perfusion, and tissue hypoxia elicited in the liver after gut I/R. These KC-mediated responses appear to involve the participation of both PAF and TNF-alpha.
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PMID:Role of Kupffer cells in gut ischemia/reperfusion-induced hepatic microvascular dysfunction in mice. 939 90


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