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)

We investigated the role of adhesion molecules in the early phase of reperfusion following cold ischemia. Livers of male Lewis rats were preserved for 0 h (group A) or 24 h in University of Wisconsin (UW) solution without additives (group B) or in UW solution with anti-ICAM-1 antibody (group C) or anti-E-selectin-1, SLe(x) and SLe(a) antibodies (group D). The livers were then reperfused with diluted rat whole blood (DWB; groups A and B). DWB containing anti-ICAM-1 and LFA-1 antibodies (group C) or DWB containing anti-L-selectin, SLe(x) and SLe(a) antibodies (group D). The reperfusion was performed at 37 degrees C for 1 h at 5 cm H2O of perfusion pressure. During reperfusion, hepatic microcirculation was assessed by monitoring portal and peripheral tissue blood flow. Bile production was significantly reduced in group B livers compared with those in group A. Anti-ICAM-1 and LFA-1 antibodies failed to improve hepatic microcirculation, whereas anti-LECAM-1, SLe(x) and SLe(a) antibodies significantly improved the microcirculation. Bile production in group C and D livers was comparable to that in group B livers. Preservation for 24 h significantly increased the release of TNF-alpha from 0.207 to 43.7 pg/g per hour during reperfusion. Monoclonal antibodies to the adhesion molecules did not suppress the release of TNF-alpha in groups C and D. Histological examination demonstrated a lack of leukocyte infiltration or thrombus in hetapic microvessels. The extent of hepatocyte necrosis did not differ among groups B, C, and D. We conclude that the microcirculatory disturbance in the early phase of reperfusion occurs as a result of the tethering of leukocytes through the interaction of the selectin family and their ligands, and that the ICAM-1-LFA-1 pathway is not involved in this step. The lack of improvement in bile production with antibodies to the selectin family and their ligands strongly suggests that other mechanisms participate in the deterioration of hepatic function.
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PMID:Impact of adhesion molecules of the selectin family on liver microcirculation at reperfusion following cold ischemia. 887 87

Cerebral ischemia is caused by reduced blood supply at the microcirculatory level. In the microvessels, the main elements of the reperfusion injury following brain ischemia are the transformation of endothelial cell-surface from anticoagulant to procoagulant property, leukocyte adhesion, sludge or clot formation. There is a paucity of information on how hemostatic factors, cytokines, lipoprotein(a) (Lp(a)) and endothelin-1 (ET-1), being responsible for ischemic/reperfusion injury, interact with human brain microvessel endothelium (HBEC). There are no data furthermore about the expression of complement proteins of HBEC influenced by cytokines or fibrinolytic factors. Previously we established optimal conditions for culturing HBEC. Cell contraction induced by thrombin, plasmin, miniplasmin was recorded. The reassembly of F-actin was observed after thrombin treatment. ICAM-1 upregulation was measured following TNF-alpha, IL-1-alpha and thrombin incubation. Plasmin and miniplasmin downregulated the ICAM-1 in our cell culture system. Lp(a) modulated the thromboresistant cell-surface by reduction of t-PA and u-PA, but PAI-1 remained unchanged. Lp(a) modulated the ET-1 production by early increasing and late decreasing, in a bimodal manner. The increased secretion of ET-1 by cytokines (TNF-alpha, IL-1-alpha) was reduced in the presence of Lp(a). Gradual increase of complement proteins (factor H, factor B, C4) was induced by cytokines. Plasmin and miniplasmin augmented a rapid increase of C4. Some factors of complex relationship between regulators and modulators of endothelial adhesion molecules have been demonstrated in a human cell culture system prepared from brain microvessel endothelium. A unified concept of sequential events of ischemia/reperfusion in the brain has not yet developed.
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PMID:Human brain microvessel endothelial cell culture as a model system to study vascular factors of ischemic brain. 889 62

Gut ischemia has been implicated in the pathogenesis of necrotizing enterocolitis. Cyclosporine A and rapamycin, both potent novel immunosuppressants which act on signal transduction pathways in CD4+ T-cells, could potentially modulate immune/inflammatory cellular reactions involved in tissue ischemia/reperfusion injury. We hypothesized that cyclosporine A and rapamycin would preserve mucosal cell function and attenuate inflammatory T-cell-mediated cellular changes associated with small bowel ischemic injury. Forty Sprague-Dawley rats underwent 60 min of gut ischemia by vascular occlusion of the superior mesenteric vessels. Animals were randomized to four groups (n = 10): cyclosporine A (CSA, 5 mg/kg/day SQ), rapamycin (RAP, 2 mg/kg/day SQ), cyclosporine A and rapamycin (C&R), and vehicle given to controls (CON). Following 1 hr of reperfusion, small bowel was harvested for xanthine oxidase (XO, units/mg protein) and maltase (MALT, mM substrate degraded/min/g protein) assays. Blood was obtained from the portal vein for tumor necrosis factor-alpha (TNF-alpha, pg/ml) assay. The results of the study are presented below (mean +/- SEM, *, P < 0.05 versus controls). (Table in text) The results indicate that cyclosporine and rapamycin each play a significant role in attenuating ischemia/reperfusion injury in the gut. These data suggest that there are cytoprotective and anti-inflammatory mechanisms of these drugs independent of T-cell signal transduction that provide some protective effect in small bowel ischemia. Furthermore, T-cell-mediated immune mechanisms may not be associated with the adverse effects of small bowel ischemia/reperfusion injury. Additional investigation will be necessary in order to define the role of T-cell-mediated immune injury in the gut and how this relates to the beneficial effect of immunosuppression in small bowel mucosal ischemic injury.
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PMID:Beneficial effects of cyclosporine and rapamycin in small bowel ischemic injury. 890 56

Defibrotide (a polydeoxyribonucleotide) and oligotide (an oligodeoxyribonucleotide) obtained from mammalian single-stranded DNA, have been demonstrated to have anti-ischemic activity in some experimental models of ischemia/reperfusion of kidney in rats. We hypothesized that their anti-ischemic activity could be related to an inhibition of leukocyte-endothelial cell adhesion and also the consequent generation of oxygen free radicals by leukocytes. We studied the in vitro adhesion of neutrophils to human umbilical vein endothelial cells under basal conditions and following neutrophil or endothelial cell activation (using 10(-7) fMLP and 500 U/ml TNF-alpha, respectively). Defibrotide and oligotide significantly inhibited neutrophil adhesion to endothelial cells (after only 1 min of drug treatment). When the anti-LFA-1 70H12 F(ab)2 monoclonal antibody was used, the drugs exerted only slight additional inhibition of the adhesion of fMLP-activated neutrophils to endothelium. These results, confirmed in NIH/3T3-ICAM-1-transfected cells, demonstrate that defibrotide and oligotide interfere with leukocyte adhesion to endothelial cells by an LFA-1-dependent mechanism.
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PMID:The anti-ischemic drugs defibrotide and oligotide analogously inhibit leukocyte-endothelial cell adhesion in vitro. 895 77

Events in the early post-transplant period have been correlated with increased renal allograft loss. Immunologic reactions and ischemic injury have been implicated in this process. While the immunologic aspects of allograft injury have been studied extensively, ischemic effects remain less well understood. To study the effects of ischemia in rats with different genetic backgrounds without the introduction of an alloimmune response, a clamp was placed on the vascular pedicle of the left kidney for 60 min. The short-term effects (1 wk) of ischemia were studied in groups of PVG (RT1c), LEW (RT1), DA (RT1a) and WR (RT1u) rats, Immunoperoxidase staining demonstrated limited infiltration of monocytes, macrophages, and T-cells accompanied by upregulation of low levels of MHC class II antigens on tubular epithelial cells, peritubular capillaries, and interstitial cells in kidneys of PVG and WF rats. Kidneys of LEW and DA rats had greater influxes of monocytes, macrophages, and T cells in addition to higher amounts of MHC class II antigens upregulation on tubular epithelium and interstitial cells. The long-term effects of ischemia were studied in kidneys of WF rats. These kidneys had a progressive increase in infiltrating T cells, monocytes, macrophages and MHC class II expression on the tubular epithelium and the interstitial cells at 14, 30, and 90 d after the ischemic insult. The differences in MHC class II expression between ischemic kidneys of PVG and LEW rats were not associated with differences in production of mRNA for IL-2, IFN-gamma, and TNF-alpha. In summary, transient renal ischemia in the absence of an allogeneic immune response triggers a progression of inflammatory responses, including leukocyte infiltration, cytokine production and MHC class II antigen upregulation which appears to be strain-dependent.
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PMID:Immunohistochemical manifestations of unilateral kidney ischemia. 899 59

Ischemic tolerance was induced in spontaneously hypertensive rats (SHR) by injection of a single dose of lipopolysaccharide (LPS) (0.9 mg/kg, i.v.) 1-7 days prior to permanent middle cerebral artery occlusion (MCAO). Infarct volume, evaluated 24 h after MCAO, was significantly reduced by LPS administration 2, 3 or 4 days prior to MCAO (22.8, 25.9 and 20.5%, respectively). The beneficial effect of LPS pre-treatment was completely nullified by concurrent administration of TNFbp. On this basis, the tolerance to ischemia induced by LPS is likely to be mediated by TNF-alpha.
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PMID:Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats. 906 75

Proinflammatory cytokines have been found to mediate part of the local and distant organ injury after ischemia and reperfusion (I/R). The anti-inflammatory cytokine interleukin-10 (IL-10) inhibits both TNF-alpha and IL-1, and we hypothesized that exogenous human IL-10 may decrease lung and soleus muscle injury after hindlimb I/R. Male Sprague-Dawley rats were randomly assigned to I/R (n = 10); I/R+IL-10 (10 micrograms i.v., n = 10), SHAM (n = 4); or SHAM+IL-10 (10 micrograms i.v., n = 4). Bilateral hindlimb ischemia was produced by tourniquet occlusion for 4 hr and all animals were sacrificed after 4 hr of reperfusion or at comparable times for the SHAMs. Soleus muscle cellular injury was determined by uptake of 99Tc pyrophosphate while soleus muscle capillary permeability, and lung capillary permeability were assessed by uptake of 125I-labeled albumin. Soleus muscle and lung neutrophil infiltration were measured with the myeloperoxidase assay. Serum samples were assessed for TNF-alpha production with the WEHI bioassay. Hindlimb I/R caused significant soleus muscle cellular injury, soleus muscle capillary injury, lung capillary injury, and lung neutrophil infiltration, Pretreatment with exogenous IL-10 significantly reduced soleus muscle capillary permeability and also reduced soleus muscle cellular injury, but not to a statistically significant degree. IL-10 administration also reduced pulmonary capillary permeability despite significantly increased lung neutrophil infiltration. Elevated TNF-alpha levels were found in 66% (4/6) rats in the I/R group versus 30% (3/10) rats in the I/R+IL-10 group. Exogenous IL-10 attenuates both local and distant organ injury after hindlimb I/R potentially independent of neutrophil infiltration.
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PMID:Exogenous human recombinant interleukin-10 attenuates hindlimb ischemia-reperfusion injury. 922 18

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

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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