UMLS:C0022116 - FACTA Search

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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 an adhesion molecule such as P-selectin may be important in the pathogenesis of stroke. However, temporal, spatial and cellular profiles of the expression of such a protein have not been fully studied. Change of immunoreactive P-selectin was examined in rat brain after transient middle cerebral artery (MCA) occlusion in comparison with that of 72 kDa heat shock protein (HSP72) which is a well known marker of cell injury. Western blot analyses were performed to ensure the selective detection of immunoreactive P-selectin and HSP72 proteins with each antibody using brain samples before and after ischemia. Temporal, spatial and cellular changes of immunohistochemical expressions of P-selectin and HSP72 were evaluated with rat brain sections at 2 and 8 h, and 1, 3 and 7 days of reperfusion after 1 h of MCA occlusion (MCAO). Hematoxylin-eosin (HE) staining was performed to evaluate brain cell damage at 3 and 7 days of reperfusion. Western blot showed a single band at molecular weights of 140 and 72 kDa for P-selectin and HSP72, respectively, only after ischemia. No significant band was observed without primary antibody. P-selectin-like immunoreactivity was not normally present in rat brain sections. However, it was expressed mainly in the post-capillary venules of the cerebral cortex and caudate in the MCA territory with a peak at 8 h to 1 day. The expression was diminished by 3 days of reperfusion. An immunoreactive HSP72 was scarcely present in the cerebral cortex and caudate of the sham control brain. However, the protein was induced in neurons of the MCA territory. The HSP72 induction was gradually intensified from 8 h with peaks at 1 day in the cortex and at 3 days in the caudate. The immunoreactivity decreased by 7 days. Histopathological study with HE staining showed no evident cell damage at 3 and 7 days of reperfusion. The present results indicate that temporal, spatial and cellular differences were present in the expressions of immunoreactive P-selectin and HSP72 proteins. P-selectin was expressed from an earlier stage of reperfusion in post-capillary venules, and the expression became maximum at the same time both in the cerebral cortex and caudate. In contrast, HSP72 induction began later in neurons and reached maximum at a different time between the cortex and caudate.
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PMID:Expressions of P-selectin- and HSP72-like immunoreactivities in rat brain after transient middle cerebral artery occlusion. 922 57

Neutrophils are important in ischemia and reperfusion injury. Multiple factors may be responsible for the adhesion of granulocytes to endothelial cells. P-selectin is a carbohydrate-binding glycoprotein that is stored preformed in endothelial cells as Weibel-Palade bodies. This preformation implies a very early role of P-selectin in the leukocyte adhesion process. Previous studies of P-selectin have not quantified its expression. The purpose of this study is to quantitate the expression and time course of P-selectin in response to renal ischemia and reperfusion injury. P-selectin was measured in 34 C57BL-6 mice after 30 minutes of occlusive left renal ischemia followed by 20 minutes, 2, 5, 10, and 24 hours of reperfusion. This was also performed in control and sham laparotomy groups. P-selectin was quantified using a new double radiolabeled 125I/131I monoclonal antibody technique and reported as percent injected dose per gram of tissue. P-selectin expression peaked at 20 minutes, plateaued up to 5 hours, and fell at 10 hours. Additionally, genetically altered mice that do not express P-selectin showed no up regulation after 5 hours of reperfusion. Pathology results confirmed significant renal injury. Renal ischemia and reperfusion injury caused significant upregulation of P-selectin. Expression of P-selectin at the short reperfusion time of 20 minutes reinforces the premise that P-selectin is one of the earliest adhesion molecules expressed. This early peak is probably caused by the release of preformed P-selectin. The delineation of these mechanisms of injury may be important in understanding and preventing renal injury in transplantation, sepsis, and shock.
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PMID:Quantification of P-selectin expression after renal ischemia and reperfusion. 924 23

Ischemic preconditioning (IPC) refers to a phenomenon in which a tissue is rendered resistant to the deleterious effects of prolonged ischemia by previous exposure to brief periods of vascular occlusion. While the beneficial effects of IPC were first demonstrated in the myocardium, it is now clear that preconditioning protects postischemic skeletal muscle, brain, and small intestine and may also occur in humans. Although first described over a decade ago, the mechanisms underlying the powerful protective effects of IPC remain uncertain. However, a growing body of evidence indicates that the beneficial actions of IPC involve the activation of adenosine A1 receptors during the period of preconditioning ischemia in most organs and species. Adenosine A1 receptor stimulation is thought to promote the translocation and activation of specific isoforms of protein kinase C1 which in turn phosphorylate as yet unidentified cellular effector molecules. In the heart, it has been suggested that ATP-sensitive potassium channels may represent important effectors of the preconditioning phenomenon. In contrast, ATP-sensitive potassium channel activation does not seem to contribute to the beneficial effects of IPC in the small bowel and seems to play only a limited role in skeletal muscle. In these peripheral tissues, the beneficial effects of IPC are related to inhibition of leukocyte adhesion and emigration. In the small intestine, IPC seems to prevent postischemic leukocyte adhesion by maintaining the bioavailability of nitric oxide (a potent endogenous anti-adhesive agent) and preventing, the expression of P-selectin (an adhesive molecule expressed by endothelial cells that is thought to modulate leukocyte rolling). In skeletal muscle, these actions are mediated by an effect of IPC to augment the production of adenosine (another potent endogenous anti-adhesive agent) during reperfusion. Thus, although adenosine-induced protein kinase C activation seems to play an important role in initiating the beneficial actions of IPC in most tissues, the effector of the preconditioning phenomenon seems to differ among tissues. Understanding the mechanisms of IPC has led to the recognition that tissues may also be preconditioned by administration of agents that act via the same signaling cascade (e.g., adenosine, bradykinin, alpha 1-adrenergic agonists). The purpose of this review is to summarize the evidence regarding the mechanisms of IPC in different organs.
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PMID:Mechanisms of ischemic preconditioning. 926 97

The objective of this study was to define the influence of hypercholesterolemia on ischemia-reperfusion (I/R)-induced leukocyte-endothelial cell adhesion and albumin leakage in rat mesenteric venules. The microvascular alterations normally elicited by I/R (leukocyte adherence and emigration, albumin leakage, and platelet aggregation) were more pronounced in hypercholesterolemic rats (compared with control rats). Monoclonal antibodies against the adhesion glycoproteins CD11/CD18 and intercellular adhesion molecule-1 attenuated the I/R-induced leukocyte adherence and emigration and albumin leakage. Leukocyte adherence, but not albumin leakage, was diminished in animals pretreated with a P-selectin-specific antibody. Platelet aggregation was reduced by antibodies directed against either P-selectin, CD18, or intercellular adhesion molecule-1, as well as a GPIIb-IIIa antagonist. These results indicate that the enhanced reperfusion-induced albumin leakage in hypercholesterolemic rats is dependent on leukocyte-endothelial cell adhesion. Furthermore, P-selectin- and CD11/CD18-dependent heterotypic and GPIIb-IIIa-mediated homotypic platelet aggregation appear to influence the extravasation of both leukocytes and albumin in postischemic venules of hypercholesterolemic rats.
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PMID:Reperfusion-induced leukocyte adhesion and vascular protein leakage in normal and hypercholesterolemic rats. 927 3

Experimental occlusion of a brain-supplying artery triggers tissue ischemia and subsequent inflammatory events that are initiated at the blood microvessel interface. Cytokine production and molecular adhesive events occur in the early moments following cerebral blood flow reduction, which underlie the transition from ischemic to inflammatory injury. Events both within the microvascular lumen and in the immediately surrounding tissue are involved. Cytokines, including TNF-alpha, IL-1 beta, IL-6, and PAF, are produced from the ischemic parenchyma and contribute to the endothelial cell expression of P-selectin, ICAM-1, and E-selectin. Platelet activation occurs paris passu and probably involves alpha-granule P-selectin to mediate PMN leukocyte-platelet interactions. Other integrin heterodimers are also involved in the early microvascular responses to ischemia. The response of the basal lamina and ECM is somewhat slower, entailing yet unproven mechanisms that most probably include the proteolytic processes of leukocyte transmigration. The modifications to microvascular structure are likely to affect both endothelial and astrocyte relationships, promote erythrocyte extravasation and hemorrhage, and contribute to tissue injury. Remodeling of the microvasculature, apparent in other tissues, involves a number of these processes. However, the enzymatic participants and regulating mechanisms are coming under study: the unraveling of regulatory mechanisms of adhesion receptor expression and their modulation, and the companion roles of integrins as mediators of structural integrity and intercellular signaling.
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PMID:Microvascular responses to cerebral ischemia/inflammation. 929 40

The dual radiolabeled monoclonal antibody technique was used to 1) define the magnitude and kinetics of P-selectin expression in murine small intestine exposed to ischemia-reperfusion (I/R), and 2) determine the factor(s) responsible for initiating this response. Within 10 min after release of a 20-min arterial occlusion, intestinal P-selectin expression increased two- to threefold compared with control values. Peak (4-fold) expression of P-selectin was noted at 5 h after reperfusion, returning to the control value at 24 h. The early (10-30 min) I/R-induced upregulation of P-selectin appears to reflect mobilization of a performed pool of the adhesion molecule, whereas the later (5 h) rise appears to be transcription dependent. The early increase in P-selectin expression was not inhibited by pretreatment with either oxypurinol (inhibits xanthine oxidase), diphenhydramine (H1-receptor antagonist), or MK-571 (leukotriene C4/D4 antagonist), nor was it blunted in transgenic mice expressing three times the normal level of copper-zinc superoxide dismutase or in mast cell-deficient mice. However, significant inhibition was noted after treatment with either MK-886 (5-lipoxygenase inhibitor) or a nitric oxide (NO) donor (diethylenetriamine/NO). These findings indicate that the early I/R-induced increase in intestinal P-selectin expression is mediated by a 5-lipoxygenase-dependent NO-inhibitable mechanism.
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PMID:Modulation of P-selectin expression in the postischemic intestinal microvasculature. 943 58

Previous studies utilizing monoclonal antibodies directed against specific leukocyte-endothelial cell adhesion proteins have suggested that neutrophils mediate endothelial cell injury in a number of vascular beds after ischemia-reperfusion (I/R). In the present study, we investigated superior mesenteric artery (SMA) vascular reactivity to acetylcholine (ACh) and sodium nitroprusside (SNP) after occlusion and reperfusion in wild-type (C57BL/6) mice and in gene-targeted mice that are deficient in either CD11/CD18, intercellular adhesion molecule 1 (ICAM-1), or P-selectin. All mice were 4 wk of age, and the SMA was occluded for 45 min and then reperfused for 45 min. Segments of SMA were isolated and suspended in organ chambers and contracted with phenylephrine (10(-5) M), and the maximal vasorelaxation to ACh (10(-6) M) and SNP (10(-6) M) was measured. SMA from sham-operated C57BL/6 mice relaxed 83.5 +/- 3.3% to ACh and 91.7 +/- 3.4% to SNP. In contrast, segments of SMA from C57BL/6 mice subjected to I/R demonstrated a marked impairment in vasorelaxation to ACh (51.3 +/- 4.7%, P < 0.01 vs. sham) without any impairment in the vasoreactivity to SNP (86.1 +/- 5.5%). In CD11/CD18-deficient mice, SMA reactivity to ACh (84.7 +/- 2.3%) and SNP (91.2 +/- 2.8%) was unaffected by I/R. Similarly, SMA rings from ICAM-1-deficient mice exhibited normal vasorelaxation to ACh and SNP with maximal vasorelaxation of 83.1 +/- 2.9 and 87.4 +/- 3.0%, respectively. We also observed profound preservation of endothelium-dependent vasorelaxation after I/R in P-selectin-deficient mice. These findings indicate that leukocyte-endothelial cell adhesion molecule deficiency is associated with the preservation of endothelium-dependent vascular responses after I/R.
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PMID:Postischemic endothelium-dependent vascular reactivity is preserved in adhesion molecule-deficient mice. 943 8

We tested whether polysaccharide fucoidin, which inhibits leukocyte rolling in the mesenteric venule, has protective effects in the rat myocardial 30-min ischemia and 6-h reperfusion injury model. Intravenous infusion of fucoidin (27 microg/kg/min from 10 min before to 6 h after reperfusion) significantly attenuated myocardial infarct size 6 h after reperfusion. In this ischemia and reperfusion heart model, expression of P-selectin (determined immunohistochemically) was observed on the venular endothelial cells in the heart 30 min after reperfusion and also was sustained after 6 h. Neutrophil infiltration as estimated by myeloperoxidase activity significantly increased 2 h after reperfusion and kept increasing with time until 6 h after reperfusion. Four-hour infusion of fucoidin after reperfusion significantly reduced neutrophil infiltration, whereas the 2-h infusion of fucoidin did not. These results indicate that neutrophil infiltration and myocardial injury are attributed to expression of P-selectin after reperfusion, and that one of the inhibitory mechanisms of fucoidin seems to be blockade of P-selectin-mediated neutrophil rolling on the vessel wall.
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PMID:Protective effects of polysaccharide fucoidin on myocardial ischemia-reperfusion injury in rats. 943 8

A growing body of evidence indicates that neutrophils play a critical role in disrupting the microvascular barrier in skeletal muscle. Recent studies from our laboratory and by others indicate that administration of antibodies directed against P-selectin, ICAM-1, or the common subunit (CD18) of CD11/CD18 was as effective as neutrophil depletion in attenuating ischemia/reperfusion (I/R)-induced microvascular barrier disruption and edema formation in skeletal muscle. These studies have important implications with regard to the pathogenesis of leg ulceration in view of our more recent work indicating that the increase in tissue pressure induced by edema formation secondary to microvascular barrier disruption may lead to the development of capillary no-reflow. The resulting maldistribution of blood flow during reperfusion exacerbates muscle injury induced by ischemia. Daflon 500 mg is a purified, micronized flavonoid fraction that exhibits a number of anti-inflammatory properties and is used clinically to treat venous insufficiency. In view of these actions and the demonstrated role of neutrophil adhesion in the pathogenesis of I/R, we sought to determine whether this agent would prevent leukocyte adhesion and microvascular barrier disruption in postischemic rat cremaster muscles and small bowel. Rats were treated with Daflon 500 mg (80 mg/kg/day by gavage) or its vehicle for 2 (cremaster studies) or 10 (mesenteric studies) days prior to the experiments. Leukocyte/endothelial cell interactions and venular protein leakage were quantitated using intravital microscopic techniques in rat cremaster muscles and mesenteries subjected to ischemia (60 min for cremaster, 20 min for mesentery) and reperfusion (60 min). The results indicated that Daflon 500 mg was as effective as the anti-adhesive monoclonal antibodies in reducing postischemic leukocyte adhesion and emigration and venular protein leakage in these models.
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PMID:Postischemic leukocyte/endothelial cell interactions and microvascular barrier dysfunction in skeletal muscle: cellular mechanisms and effect of Daflon 500 mg. 947 39

A growing body of experimental evidence suggests that neutrophilic polymorphonuclear leukocyte (PMN)-endothelial cell interactions play a critical role in the pathophysiology of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. The objective of this study was to directly determine whether the expression of endothelial cell adhesion molecules is enhanced in a model of NSAID-induced gastropathy. Gastropathy was induced in male Sprague-Dawley rats via oral administration of indomethacin (Indo, 20 mg/kg). Lesion scores, blood-to-lumen clearance of 51Cr-EDTA (mucosal permeability), and histological analysis (epithelial necrosis) were used as indexes of gastric mucosal injury. Gastric mucosal vascular expression of intercellular adhesion molecule 1 (ICAM-1) or P-selectin were determined at 1 and 3 h after Indo administration using the dual radiolabeled monoclonal antibody (MAb) technique. For some experiments, a blocking MAb directed at either ICAM-1 (1A29) or P-selectin (RMP-1) or their isotype-matched controls was injected intravenously 10 min before Indo administration. We found that P-selectin expression was significantly increased at 1 h but not 3 h after Indo administration, whereas ICAM-1 expression was significantly increased at both 1 and 3 h after Indo treatment. The blocking ICAM-1 and P-selectin MAbs both inhibited Indo-induced increases in lesion score, mucosal permeability, and epithelial cell necrosis. However, the Indo-induced gastropathy was not associated with significant PMN infiltration into the gastric mucosal interstitium, nor did Indo reduce gastric mucosal blood flow. We propose that NSAID-induced gastric mucosal injury may be related to the expression of P-selectin and ICAM-1; however, this mucosal injury does not appear to be dependent on the extravasation of inflammatory cells or mucosal ischemia.
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PMID:ICAM-1 and P-selectin expression in a model of NSAID-induced gastropathy. 948 76

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