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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of platelet-activating factor as a potential mediator of hepatic inflammatory injury associated with liver ischemia/reperfusion was investigated using a partial no-flow model in rats in vivo. Platelet-activating factor levels of livers from sham-operated rats and from animals experiencing hepatic reperfusion for less than 6 hr were very low. They were observed to increase significantly after 12 hr of reperfusion and reached peak levels after a 24-hr reperfusion period, a time when maximal hepatic injury and inflammation occurred. Treatment of experimental rats with WEB2170, a platelet-activating factor receptor antagonist, attenuated the hepatic injury and inflammation, as evidenced by decreases in plasma ALT and in hepatocyte necrosis and neutrophil infiltration. Both inactivation of Kupffer cells with gadolinium chloride and inhibition of the formation of reactive oxygen species with allopurinol reduced platelet-activating factor production in the liver, whereas induction of neutropenia had no effect, suggesting that interaction of Kupffer cells with oxygen-derived free radicals may be a plausible mechanism for hepatic platelet-activating factor accumulation. It is concluded that platelet-activating factor contributes to the inflammatory consequences of ischemia/reperfusion underlying late-phase hepatic injury.
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PMID:Inflammation and platelet-activating factor production during hepatic ischemia/reperfusion. 142 62

Lower torso ischemia leads to acute respiratory failure, an event associated with the accumulation of inflammatory cells in the lungs. This study tests whether ischemia-induced eicosanoid synthesis leads to polymorphonuclear leukocyte (PMN) accumulation in the lungs. Anesthetized rats (N = 51) were randomized into five groups: nonischemic sham rats (N = 10); the remaining four groups were rats made ischemic for 4 hours with bilateral thigh tourniquets treated just before tourniquet release with saline vehicle (N = 17): the thromboxane (Tx) synthase inhibitor OKY-046 (Ono Pharmaceutica, Osaka, Japan) 2 mg/kg intravenously every 2 hours (N = 8); the lipoxygenase inhibitor diethylcarbamazine (DEC) (Sigma, St. Louis, MO) 0.2 mg/kg/min intravenously (N = 8); the platelet-activating factor receptor antagonist SRI (Sandoz Inc., East Hanover, NJ) 63-072 3 mg/kg intravenously every 30 minutes (N = 8). Four hours after ischemia, plasma TxB2 levels in the ischemic placebo-treated group was 3570 +/- 695 pg/mL, compared with 495 +/- 73 pg/mL in sham rats (p less than 0.001). Lung microscopy showed foci of proteinaceous exudate in alveoli and 121 +/- 10 PMN/20 high power fields (HPF) compared with 59 +/- 9 PMN/20 HPF in the sham group (p less than 0.001). One day after ischemia PMN accumulations remained elevated at 119 PMN/20 HPF. Pretreatment with OKY-046 led to reduced TxB2 levels of 149 +/- 17 pg/mL, normal lung histology, and 83 +/- 13 PMN/20 HPF, a value similar to that of the sham group and lower than that of the placebo-treated group (p less than 0.05). Treatment with DEC yielded TxB2 levels of 1419 +/- 492 pg/mL, which was lower than that of the placebo group (p less than 0.05) but higher than that of the sham group (p less than 0.05). Microscopy showed normal lungs with 79 +/- 7 PMN/20 HPF lower than the placebo group (p less than 0.05). SRI 63-072 did not inhibit Tx synthesis or leukosequestration in the lungs. Platelet counts decreased in all groups relative to sham animals (p less than 0.05). The results indicate that Tx synthesis induced by ischemia moderates PMN accumulations in the lungs. Inhibition of lipoxygenase is believed to prevent PMN accumulations both by limiting leukotriene-induced Tx synthesis as well as by limiting production of chemoattractants.
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PMID:Pulmonary leukosequestration induced by hind limb ischemia. 360 41

During the last decade, evidence increased that microcirculatory disorders play a pivotal role in the development of mucosal injury, and, hence, formation of gastric ulcer. Mucosal microcirculation is altered at least by two distinct mechanisms: Stimulation of acid secretion leads to a rise of blood flow in the acid-secreting areas, and, concomitantly, due to a steal-phenomenon to a decrease of mucosal capillary perfusion of the antrum, which results in temporary ischemia. In addition, surface noxae-induced release of potent mediators, such as histamine, leukotrienes, thromboxane, platelet-activating factor and reactive oxygen metabolites cause vasoconstriction, capillary stasis and increase of microvascular permeability (loss of endothelial integrity), which aggravate mucosal injury. Therefore, therapeutic strategies should consider leukotriene-synthesis inhibitors, histamine-, thromboxane- and platelet-activating factor receptor antagonists, oxygen radical scavengers, as well as counteracting mediators and hormones, such as prostaglandins and somatostatin, inasmuch as these compounds have been shown to additionally prevent mucosal microvascular injury, in particular capillary perfusion failure and loss of endothelial integrity, during gastric ulcer formation.
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PMID:[Microcirculation of gastric mucosa in pathogenesis of stomach ulcer]. 751 63

Although platelet-activating factor has been implicated in the pathogenesis of neutrophil-induced reperfusion injury, it has other mechanisms of direct deleterious hemodynamic effect. In this study we evaluated the definitive role of platelet-activating factor in myocardial reperfusion injury. Porcine hearts that underwent 60 minutes of normothermic ischemia with cardioplegia and 60 minutes of reperfusion under cardiopulmonary bypass were divided into three groups according to the methods of 15 minutes of controlled reperfusion: whole blood reperfusion group (n = 6), leukocyte-depleted reperfusion group (n = 6), and platelet-activating factor receptor antagonist (CV-3988) group (n = 6). At 60 minutes of reperfusion, the percentage of recovery of maximum slope of the pressure-volume relationship measured with intraventricular balloon, malondialdehyde value in coronary sinus blood, tissue adenosine triphosphate, and percentage of spontaneous defibrillation were evaluated. The receptor antagonist group showed significantly better recovery of maximum slope of the pressure-volume relationship than did the whole blood reperfusion group. Moreover, the receptor antagonist group showed significantly less release of malondialdehyde in the coronary sinus, higher values of adenosine triphosphate in the myocardium, and a higher percentage of spontaneous defibrillation than did the whole blood reperfusion group. On the other hand, the leukocyte-depleted reperfusion group showed no significant differences of maximum slope of the pressure-volume relationship, malondialdehyde, adenosine triphosphate, or spontaneous defibrillation as compared with the whole blood group. These results suggest that platelet-activating factor receptor antagonist attenuated severe damage in whole blood reperfusion of the myocardium as compared with leukocyte-depleted reperfusion, which also suggests that platelet-activating factor may play a more important role in myocardial reperfusion injury than do neutrophils.
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PMID:Platelet-activating factor plays an important role in reperfusion injury in myocardium. Efficacy of platelet-activating factor receptor antagonist (CV-3988) as compared with leukocyte-depleted reperfusion. 796 80

The use of intravital fluorescence microscopy in the models of the hamster dorsal skin fold chamber and the ear of the hairless mouse allows for the quantitative analysis of post-ischemic microvascular reperfusion injury in striated muscle and skin. Prolonged periods of ischemia (4 hours in striated muscle and 6 hours in skin) are associated with 1) perfusion failure of nutritive capillaries at the onset of reperfusion (no-reflow) and 2) activation, accumulation and microvascular adherence of white blood cells, formation of reactive oxygen metabolites and release of potent mediators (leukotrienes, platelet-activating factor) with the consequence of increased microvascular permeability due to the loss of endothelial integrity, interstitial edema and cell damage (reflow-paradox). Prophylactic and/or therapeutic regimens may, therefore, include improvement of capillary perfusion by hemodilution, and inhibition of leukocyte adherence, radical formation and mediator release by appropriate counteracting compounds, including anti-oxidants, antibodies directed against adhesion molecules, leukotriene synthesis inhibitors and platelet-activating factor receptor antagonists.
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PMID:In vivo analysis of microvascular reperfusion injury in striated muscle and skin. 796 63

The Pulsinelli-Brierley four-vessel occlusion model was used to study the consequences of hyperglycemic ischemia and reperfusion. Rats were subjected to either 30 min of normo- or hyperglycemic ischemia or 30 min of normo- or hyperglycemic ischemia followed by 60 min of reperfusion. In some animals, 2 mg/kg BN 50739, a platelet-activating factor receptor antagonist, was administered intraarterially either before or after the ischemic insult. The changes in mitochondrial membrane free fatty acid levels, phosphatidylcholine fatty acyl composition, and thiobarbituric acid-reactive material (TBAR) content plus the mitochondrial respiratory control ratio (RCR) were monitored. When the platelet-activating factor antagonist was present during normoglycemia, (a) the mitochondrial free fatty acid release both during and after ischemia was slowed, (b) reacylation of phosphatidylcholine following ischemia was promoted, and (c) TBAR accumulation during and following ischemia was decreased. The detrimental effects of hyperglycemia were muted when BN 50739 was present during ischemia. The RCR was preserved and phosphatidylcholine hydrolysis during ischemia was decreased. TBAR levels were consistently higher in hyperglycemic brain mitochondria both during and after ischemia. The RCR correlated directly with mitochondrial phosphatidylcholine polyunsaturated fatty acid content during ischemia and reperfusion. BN 50739 protection of mitochondrial membranes in brain may be influenced by tissue pH.
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PMID:Hyperglycemic damage to mitochondrial membranes during cerebral ischemia: amelioration by platelet-activating factor antagonist BN 50739. 928 46

1 The reperfusion of ischemic tissues may be associated with local and systemic inflammation that prevents the full benefit of blood flow restoration. The present study aimed to confirm a role for platelet-activating factor receptor(s) (PAFR) during ischemia and reperfusion injury by using genetically modified mice deficient in the PAFR (PAFR(-/-) mice) and to evaluate comparatively the effectiveness of pharmacological treatment using the PAFR antagonist UK-74,505 (modipafant). 2 The reperfusion of the ischemic superior mesenteric artery (SMA) induced marked local (intestine) and remote (lungs) tissue injury, as assessed by the increase in vascular permeability, neutrophil influx and intestinal hemorrhage and in the production of TNF-alpha. There was also a systemic inflammatory response, as shown by the increase in serum TNF-alpha concentrations and marked reperfusion-associated lethality. 3 After reperfusion of the ischemic SMA, PAFR(-/-) mice had little tissue or systemic inflammation and lethality was delayed, but not prevented, in these mice. Interestingly, the reperfusion-associated increases in tissue concentrations of IL-10 were significantly greater in PAFR(-/-) than wild-type mice. 4 Pretreatment with PAFR antagonist UK-74,505 (1 mg kg(-1)) markedly prevented tissue injury, as assessed by the increase in vascular permeability, neutrophil accumulation, hemorrhage and TNF-alpha concentrations in the intestine and lungs. In contrast, UK-74,505 failed to affect reperfusion-associated lethality and increases in serum TNF-alpha when used at 1 mg kg(-1). 5 Reperfusion-associated lethality and increase in serum TNF-alpha were only affected when a supra-maximal dose of the antagonist was used (10 mg kg(-1)). At this dose, UK-74,505 also induced a marked enhancement of reperfusion-associated increases in tissue concentrations of IL-10. However, at the same dose, UK-74,505 failed to prevent reperfusion-associated lethality in PAFR(-/-) mice any further. 6 The present studies using genetically modified animals and a receptor antagonist firmly establish a role of PAFR activation for the local, remote and systemic inflammatory injury and lethality which follows reperfusion of the ischemic SMA in mice. Moreover, it is suggested that high doses of PAFR antagonists need to be used if the real efficacy of these compounds is to be tested clinically.
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PMID:Role of PAF receptors during intestinal ischemia and reperfusion injury. A comparative study between PAF receptor-deficient mice and PAF receptor antagonist treatment. 1281 96

Ginkgolide K, a natural platelet-activating factor receptor antagonist, was isolated from the leaves of Ginkgo biloba. However, little is known about its neuroprotective effect in ischemia-reperfusion (I/R)-induced cerebral injury. Hence, the present study was carried out to investigate the effect of ginkgolide K on neuroprotection and the potential mechanisms in the rat I/R model induced by middle cerebral artery occlusion (MCAO). The rats were pretreated with ginkgolide K 2, 4 and 8 mg/kg (i.v.) once a day for 5 days before MCAO. Neurological deficit score (NDS), brain water content, 2,3,5-triphenyltetrazolium chloride (TTC) staining and pathology of brain tissue, as well as indexes of oxidative stress [superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS)] were measured at 24 h after ischemia. The results indicated that pretreatment with ginkgolide K significantly diminished the volume of infarction and brain water content, and improved NDS. Moreover, ginkgolide K markedly reversed the level of MDA, NO, NOS and SOD to their normal state in serum or cerebral ischemic section. In addition, hematoxylin and eosin staining showed the neuronal injury was significantly improved after being pretreated with ginkgolide K. These findings demonstrate that ginkgolide K exhibits neuroprotective properties through its antioxidative action in MCAO rats.
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PMID:Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats. 2161 9