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)

In the present study, the cardioprotective effects of insulin-like growth factor I (IGF-I) were examined in a murine model of myocardial ischemia reperfusion (i.e., 20 min + 24 hr). IGF-I (1-10 micrograms per rat) administered 1 hr prior to ischemia significantly attenuated myocardial injury (i.e., creatine kinase loss) compared to vehicle (P < 0.001). In addition, cardiac myeloperoxidase activity, an index of neutrophil accumulation, in the ischemic area was significantly attenuated by IGF-I (P < 0.001). This protective effect of IGF-I was not observed with des-(1-3)-IGF-I. Immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated markedly increased DNA fragmentation due to programmed cell death (i.e., apoptosis) compared to nonischemic myocardium. Furthermore, IGF-I significantly attenuated the incidence of myocyte apoptosis after myocardial ischemia and reperfusion. Therefore, IGF-I appears to be an effective agent for preserving ischemic myocardium from reperfusion injury and protects via two different mechanisms--inhibition of polymorphonuclear leukocyte-induced cardiac necrosis and inhibition of reperfusion-induced apoptosis of cardiac myocytes.
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PMID:Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. 764 33

The objective of this study was to determine the role of cyclosporin A (CsA) on cold-restraint-induced gastric lesions. Animals were subjected to 3 h immobilization at 4 degrees C in plastic restraining devices following a starvation period of 48 h. Gastric samples were obtained for the measurement of myeloperoxidase (MPO) activity, an index of number of peroxidase positive cells and thiobarbituric acid-reactive substances (TBARS; lipid peroxidation). Animals were pretreated with CsA which is a potent immunosuppressant and inhibits ischemia/reperfusion-induced polymorphonuclear leukocyte (PMN) infiltration. Cold-restraint administration significantly elevated the tissue MPO activity and TBARS formation. CsA pretreatment significantly reduced the severity of cold-restraint-induced gastric lesions while attenuating the elevated MPO measurements observed during cold-restraint administration. Animals rendered neutropenic with antineutrophil serum (ANS) exhibited significantly less gastric mucosal injury normally observed after cold-restraint stress. Neither CsA nor ANS treatment effected the elevated TBAR levels, indicating that PMNs are not involved in the lipid peroxidation process observed after cold-restraint stress. In conclusion, the results of this study indicate that CsA is capable of inhibiting cold-restraint-induced gastric mucosal injury and can attenuate the cold-restraint-induced increases in gastric MPO measurements. Our results also indicate that PMNs may be the important mediators of cold-restraint-induced gastric lesions.
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PMID:Cyclosporin A reduces the severity of cold-restraint-induced gastric lesions: role of leukocytes. 765 47

SOD is the main detoxifying enzyme of OFRs which have been mainly purported to participate in ischaemia revascularization lesions. A study was made of the behaviour of SOD during ischaemia and the response to pharmacological doses of SOD in Wistar rats in which ischaemia was induced by 90 min of clamping and followed by revascularization. SOD levels were determined in the intestinal wall, evaluating the degree of infiltration of neutrophils, leucocytes and monocytes by immunohistochemical methods. Ischaemia led to a significant decrease in intestinal wall SOD levels (p = 0.003). The administration of pharmacological doses of SOD was observed to improve survival of the animals (p = 0.001) and significantly decreased the infiltration of leucocytes only during revascularization measured by MPO and LCA. Beneficial effects of SOD could be explained by its effect as scavenger of OFRs and by its action on the neutrophil infiltration.
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PMID:Superoxide dismutase (SOD) and neutrophil infiltration in intestinal ischaemia-revascularization. 765 5

To examine the role of neutrophils, their presence and the degree of infiltration, as important determinants of ischemia and reperfusion injury of the liver, male Sprague-Dawley rats were subjected to 60 and 90 min of total-liver ischemia. The presence of neutrophils, assessed by the measurement of liver tissue myeloperoxidase (MPO), and the degree of neutrophil liver infiltration, determined by the naphthol AS-D chloroacetate esterase technique, correlated well with animal survival and response to FK506 and cyclosporine administration. Lipid peroxidation, measured by the malondialdehyde (MDA) test in liver tissue, was another factor closely linked with liver function and survival. Pretreatment with FK506 (0.3 mg/kg) and CsA (5 mg/kg) was given at 4 hr and 1 hr before ischemia and at the time of reperfusion. Control ischemic animals showed increased neutrophil liver infiltration, high MPO and MDA liver levels, and diminished overall survival. FK506 and CsA-treated animals had better survival and diminished neutrophil liver infiltration, as well as MPO and MDA levels. The mechanism by which FK506 and CsA protected the animals from severe liver ischemic injury is unknown. Our data indicated that the presence and the degree of infiltration of neutrophils were important components of liver ischemia/reperfusion injury in the rat. So it is possible that one of the fundamental effects of the FK506 and CsA might be through the inhibition of the presence and infiltration of neutrophils in liver tissue.
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PMID:Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. 768 32

Ischemia in rat hind limbs followed by reperfusion results in local as well as remote organ (lung) injury characterized by increased vascular permeability (125I-labeled bovine serum albumin leakage) and hemorrhage (51Cr-labeled rat erythrocytes extravasation) in skeletal muscle and lung, together with an associated increased tissue content of myeloperoxidase, reflecting neutrophil accumulation. Within 60 minutes of reperfusion following ischemia, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6 plasma levels increased significantly, reaching maximum levels after 2 hours of reperfusion. Polyclonal antibodies to TNF-alpha and IL-1 provided significant protection against vascular injury in both muscle and lung. These results were confirmed by the use of soluble TNF-alpha receptor and IL-1 receptor antagonist. In rat lungs following ischemia and reperfusion, there was immunohistochemical evidence of E-selectin expression in the lung vasculature; this expression was blocked by treatment of animals with anti-TNF-alpha. These data indicate that both local (hind limb) and remote (lung) organ injury after ischemia/reperfusion requires participation of TNF-alpha and IL-1. The cytokines may, in part, be involved in the up-regulation of endothelial adhesion molecules.
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PMID:Requirements for tumor necrosis factor-alpha and interleukin-1 in limb ischemia/reperfusion injury and associated lung injury. 768 84

It has been proposed that the reduction in mortality in animal models of sepsis by activated protein C (APC) is mediated by an antiinflammatory property rather than the well-characterized anticoagulant action. Human recombinant APC was examined for potential antiinflammatory activity in the pentobarbital-anesthetized rat. In the dermal reversed passive Arthus model, APC (20.0 mg/kg/h, i.v.) elevated clotting time 10-fold 3 h after the Arthus challenge, at which time, the wet-weights from Arthus dermal samples in APC rats (120.0 +/- 1.5 mg, n = 10) did not differ from controls (120.1 +/- 1.5 mg, n = 10) but were 30% heavier than remote noninflamed skin (92.0 +/- 2.0 mg, n = 10), indicating that APC treatment did not diminish tissue edema associated with immune-complex deposition. Skin-lesion myeloperoxidase (neutrophil marker enzyme) activities from APC rats were not significantly different from controls but was 21-fold more than remote noninflamed skin, indicating that APC treatment did not diminish dermal recruitment of neutrophils. In the intestinal ischemia/reperfusion model, 1 h complete occlusion of the superior mesenteric artery and an additional 4 h reperfusion was associated with a 2.87-fold increase in lung myeloperoxidase activity compared to sham-operated rats. APC (1.0 mg/kg/h, i.v.) did not diminish the elevation in this index of lung neutrophil sequestration. In conclusion, APC did not produce an antiinflammatory effect in the rat models used.
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PMID:Activated recombinant human protein C does not attenuate recruitment of neutrophils in rat models of acute inflammation. 771 66

The dose-related cardioprotective efficacy of the thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist, ifetroban (BMS-180291), was investigated in an anesthetized ferret model of myocardial ischemia (90 min) followed by reperfusion (5 h). Treatment was begun at either the 75th minute of ischemia or 5 min after initiating reperfusion. The magnitude of TP receptor blockade was evaluated by ex vivo platelet function. Additional experiments in ferrets tested the antithrombotic potency of ifetroban as an inhibitor of thrombotic cyclic flow reduction (CFR) in the stenosed abdominal aorta (Folts model). Continuous ifetroban infusions of 0.03, 0.1 and 0.3 mg/kg/h reduced myocardial infarct size from 22% of the left ventricle in vehicle-control ferrets to 20, 12 and 9%, respectively. These represented reductions in infarct size of 8, 43 and 56%. Delaying initiation of treatment with high-dose ifetroban until 5 min into reperfusion also significantly reduced infarct size by 45%. High-dose ifetroban treatment did not prevent neutrophil (PMNL) accumulation measured as tissue myeloperoxidase activity in infarcted tissue. At the end of the 5-hour reperfusion period, the low, medium and high doses produced 90, 98 and 98% blockade of platelet TP receptors, respectively, measured as inhibition of ex vivo platelet shape change responses to U-46,619. Ifetroban inhibited thrombotic CFR at a threshold dose of 0.03 +/- 0.004 mg/kg, which antagonized 92% of ferret platelet TP receptors. Thus, ifetroban exhibited cardioprotective and antithrombotic activities and was effective at doses producing > 90% TP receptor blockade. Cardioprotective activity was not associated with any reductions of PMNL accumulation in infarcted tissue and was demonstrable even when treatment was delayed until 5 min after initiation of reperfusion.
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PMID:Dose-related cardioprotection by ifetroban in relation to inhibition of thrombosis and ex vivo platelet function. 771 79

Neutrophils have been identified to play a major role in ischemia/reperfusion injury through several mechanisms. Neutrophil migration into reperfused gut may reduce bacterial translocation, but may also enhance the reperfusion injury. Ethanol ingestion impairs cutaneous chemotaxis, but its effects on neutrophil migration to postischemic small bowel are unknown. This study investigates the effects of ethanol on small bowel accumulation of neutrophils after ischemia/reperfusion. Ninety-five rats were divided into five groups; normal control, sham operation, ethanol-sham, ischemia, and ethanol-ischemia groups. Ethanol was given once acutely by gavage (3 g/kg, 20% solution) to the animals in the ethanol-sham and the ethanol-ischemia groups 4 hr before ischemic injury. Ischemia was produced for 1 hr by placing a vessel loop around the superior mesenteric vessels. After 1 hr, 87% of animals had gut ischemia and the loop was removed. Three hours later the small bowel was examined for necrosis and the reperfused viable small bowel was extirpated for measurement of neutrophil infiltration by colorimetric assay for myeloperoxidase (MPO), an enzyme restricted to neutrophils. Both ethanol and ischemia/reperfusion produced significant independent increase in the MPO activity. When ethanol was given prior to ischemia, the MPO activity was further increased by statistically significant margin. The present study demonstrated that ethanol enhanced the effects of gut ischemia/reperfusion injury on PMN accumulation into the intestinal wall. These observations suggest that ethanol may potentiate ischemic injury to the gut and lead to increased problems when gut blood flow is significantly impaired.
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PMID:Ethanol ingestion potentiates PMN migration into small intestine after ischemia. 772 15

Neutrophils comprise a group of leukocytes that play a pivotal role in inflammation and vascular diseases like ischemia/reperfusion. These activated phagocytic cells are drawn to the site of injury, secreting superoxide and other oxidants derived from the formation of this free radical. This series of events frequently results in localized tissue damage. Surprisingly, free radical scavengers frequently offer only minimal relief. Why this is so may be due, in part, to our limited understanding of mechanisms that govern generation of free radicals in these settings. Although the metal ion-catalyzed Haber-Weiss reaction is considered the classical pathway for neutrophil-derived hydroxyl radical, an alternative mechanism, such as the myeloperoxidase-dependent pathway, may undoubtedly contribute to the formation of this free radical by stimulated neutrophils. In this study, we explored this possibility by investigating the role of different classes of anti-inflammatory drugs to ameliorate hydroxyl radical generation via the myeloperoxidase-dependent pathway. In this paper, we report that meclofenamic acid inhibited myeloperoxidase-dependent hydroxyl radical generation through scavenging of hypochlorous acid and not by direct inhibition of myeloperoxidase. The importance of these results with regard to the clinical efficacy of this anti-inflammatory compound remains to be determined as studies into the significance of myeloperoxidase-dependent hydroxyl radical formation in inflammatory tissue injury continue.
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PMID:Effect of anti-inflammatory drugs on myeloperoxidase-dependent hydroxyl radical generation by human neutrophils. 774 88

Investigations were carried out to determine the antiulcer effects of silymarin, the hepatoprotective principle of Silybum marianum L. Gaertn., in gastric injury induced by ischemia-reperfusion and its effects on mucosal myeloperoxidase activity, an index of polymorphonuclear leukocyte infiltration, after injury in rats. These results were compared with those from rats that received allopurinol, an inhibitor of xanthine oxidase and with those from rats made neutropenic by prior administration of dexamethasone and methotrexate. Pretreatment with silymarin prevented post-ischemic mucosal injury. The mean ulcer indexes (U.I.) of rats treated with 25, 50 mg, and 100 mg silymarin/kg body weight (4.79 +/- 0.75, 4.50 +/- 0.81, and 3.63 +/- 0.74, respectively) were significantly lower (p < 0.05, 0.05, and p < 0.005) than that of control rats. Allopurinol was considerably more potent in reducing the U.I. than silymarin, with a calculated U.I. of 2.33 +/- 0.45, p < 0.001. These protective effects were specifically related to a reduction in the number of neutrophils in the gastric mucosa. Reduction in the numbers of circulating neutrophils by treating rats with methotrexate (MPO level of 7.2 x 10(-2) +/- 0.56 x 10(-2)U/mg wt) and dexamethasone (MPO level of 6.97 x 10(-2) +/- 0.68 x 10(-2)U/mg wt) also resulted in a significant reduction in the susceptibility to gastric damage induced by ischemia-reperfusion. These results suggest that neutrophils play an important role in the gastric mucosal dysfunction associated with ischemia-reperfusion. These findings also indicate that the inhibitory effects of silymarin on neutrophil function may contribute significantly to its gastroprotective actions.
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PMID:Gastroprotection induced by silymarin, the hepatoprotective principle of Silybum marianum in ischemia-reperfusion mucosal injury: role of neutrophils. 775 16


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