Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although cardiac ischemia is usually characterized as a disease of the myocyte, it is clear that the vasculature, and especially endothelial cells, is also a major target of this pathology. Indeed, using a rat model of ischemia/reperfusion, we were able to detect severe endothelial dysfunction (assessed as a decreased response to acetylcholine) after acute or chronic reperfusion. Given the essential role of the endothelium in the regulation of vascular tone, as well as platelet and leukocyte function, such a severe dysfunction could lead to an increased risk of vasospasm, thrombosis and accelerated atherosclerosis. This dysfunction can be prevented by free radical scavengers and by exogenous nitric oxide. Endothelial dysfunction can also be prevented by preconditioning with brief periods of intermittent ischemia, thus extending to coronary endothelial cells the concept of endogenous protection previously described at the myocyte level. Experiments performed on cultured cells showed that the endothelial protection induced by free radical scavengers or by preconditioning was due to a lesser expression of endothelial adhesion molecules such as intercellular adhesion molecule-1, leading to a lesser adhesion of neutrophils to endothelial cells. Identification of the mechanisms of this protection may lead to the development of new strategies aimed at protecting the vasculature in ischemic heart diseases.
 ...
PMID:Coronary endothelial dysfunction after ischemia and reperfusion: a new therapeutic target? 1115 Oct 23

Cerebral ischemia is accompanied by a marked inflammatory reaction that is initiated by ischemia-induced expression of cytokines, adhesion molecules, and other inflammatory mediators, including prostanoids and nitric oxide. Preclinical studies suggest that interventions that are aimed at attenuating such inflammation reduce the progression of brain damage that occurs during the late stages of cerebral ischemia. In particular, strategies that block the activity of inflammation-related enzymes, such as inducible nitric oxide synthase and cyclo-oxygenase-2, reduce ischemic damage with an extended therapeutic window. Although a clinical trial using murine antibodies against intercellular adhesion molecule-1 did not show benefit in patients with ischemic stroke, recent data indicate that immune activation induced by the heterologous protein may have played an important role in the failure of this trial. Therefore, there is a strong rationale for continuing to explore the efficacy of anti-inflammatory therapies in the treatment of the late stages of cerebral ischemia.
 ...
PMID:Cerebral ischemia and inflammation. 1117 23

PNA+Tempol, albumin containing conjugated (polynitroxyl albumin; PNA) and free (4-hydroxyl-2,2,6,6-tetramethyl-piperidinyl-1-oxyl; Tempol) nitroxide may protect against injury caused by reactive oxygen species. Therefore, the actions of PNA+Tempol on liver injury and inflammation induced by hepatic ischemia and reperfusion (I/R) were examined. Rats were subjected to 1 h ischemia followed by 24 h reperfusion in the absence (I/R) or presence of PNA+Tempol (25%; 15 mL/kg, i.v.) (I/R+PNA+Tempol) or human serum albumin (23%; 13.5 mL/kg, i.v.) (I/R+HSA). Test solutions were administered prior to and for 2 h during reperfusion. Sham-operated rats underwent surgery with neither ischemia nor infusion. I/R+PNA+Tempol rats had significantly less liver injury and inflammation than I/R rats. I/R+PNA+Tempol livers exhibited focal lesions whereas I/R livers exhibited global necrosis. Likewise, plasma ALT activity was significantly lower in I/R+PNA+Tempol rats. PNA+Tempol reduced I/R-induced neutrophil accumulation and intercellular adhesion molecule-1 (ICAM-1) expression. HSA did not alter I/R-induced liver injury or inflammation. Sham-operated rats exhibited normal liver morphology and no inflammation. Attenuation of I/R liver injury by PNA+Tempol may be mediated by its effect on inflammation, the major contributor to I/R injury. Reduction of inflammation by PNA+Tempol is most likely due to the antioxidative nature of the nitroxides.
 ...
PMID:Polynitroxyl albumin plus tempol attenuates liver injury and inflammation after hepatic ischemia and reperfusion. 1119 30

Adhesion of neutrophil to the endothelium and subsequent transmigration has been reported to contribute to progression of focal ischemia. Hypothermia has been known to attenuate ischemic insult through various mechanisms of action. The authors evaluated the effect of hypothermia on expression of intercellular adhesion molecule-1 (ICAM-1) protein and on transmigration of neutrophil with immunohistochemical method. Transient focal ischemia model in rats was employed, and animals received 2 h of either normothermic or hypothermic ischemia. To confirm the effectiveness of hypothermia on neuroprotection, cortical infarct area was compared between the two groups. Our results demonstrated that hypothermia reduced both the number of microvessels expressing ICAM-1 and that of neutrophils migrating into ischemic tissue. Comparison of cortical infarct area showed persistent protective effect. This study indicates that reduction of ICAM-1 expression and subsequent reduction of migrating neutrophil in hypothermia can contribute to attenuation of ischemic damage.
 ...
PMID:Intra-ischemic hypothermia attenuates intercellular adhesion molecule-1 (ICAM-1) and migration of neutrophil. 1121 Apr 24

The chronological expression (over 24 h) of two adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) and CD11b/CD18 (Mac-1)] and the extent of liver damage, including injury to sinusoidal endothelial cells (SECs) and hepatocyte apoptosis, were investigated under two conditions of rat liver ischemia-reperfusion (I/R) injury: reversible (30 min) and fatal I/R (60 min). The chronological profiles of upregulation of ICAM-1 on hepatocytes and Mac-1 showed changes in parallel with the other liver damage parameters, and the extent of upregulation and various parameters of liver injury were more advanced in the 60-min I/R group. Paradoxically, the degree of ICAM-1 upregulation of SECs decreased significantly in the 60-min I/R group vs. the 30-min I/R group. Repression of hepatocyte apoptosis by administration of the caspase inhibitor ZVAD-fmk resulted in attenuation of neutrophil infiltration and liver injury. These findings indicate that 1) neutrophil infiltration is involved in the development of liver I/R injury; 2) interaction between ICAM-1 on SECs and Mac-1 on neutrophils is not an essential step for neutrophil transmigration through the endothelial layer because SECs, specifically, were impaired in the early stages of liver I/R injury; 3) the role of ICAM-1 and Mac-1 is to adhere neutrophils firmly to hepatocytes and activate neutrophils; and 4) excessive parenchymal apoptosis may be the signal for the neutrophil-induced inflammatory and necrotic reaction.
 ...
PMID:Mac-1 (CD11b/CD18) and intercellular adhesion molecule-1 in ischemia-reperfusion injury of rat liver. 1144 39

Our previous study demonstrated that the combination of mannosylated superoxide dismutase (Man-SOD) and succinylated catalase (Suc-CAT), both of which are designed to be targeted to liver nonparenchymal cells, is a promising approach to prevent the initial phase of hepatic ischemia/reperfusion injury induced by occlusion of the portal vein for 30 min followed by a 1-h reperfusion in mice. In this study, the preventive effects of these agents were examined on late-phase injury mediated by infiltrating neutrophils, a more severe condition than the initial one. Administration of Suc-CAT alone or with Man-SOD to mice undergoing hepatic ischemia/reperfusion significantly suppressed the expression of intercellular adhesion molecule-1 along the hepatic sinusoid and prevented neutrophil infiltration in the liver. Man-SOD and Suc-CAT also prevented the increase in plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase activities after reperfusion lasting 3 and 6 h. Histological evaluation of liver tissues confirmed the efficacy of this treatment, suggesting that these SOD and catalase derivatives have the ability to suppress neutrophil-induced hepatic injury. These results demonstrate that targeted delivery of antioxidant enzymes to liver nonparenchymal cells is a promising approach to reducing the reactive oxygen species produced by Kupffer cells and neutrophils infiltrating into the tissue. Since Suc-CAT is partially taken up by hepatocytes via a catalase-specific uptake mechanism, such a fraction could also be involved in its preventive effect against the injury.
 ...
PMID:Prevention of neutrophil-mediated hepatic ischemia/reperfusion injury by superoxide dismutase and catalase derivatives. 1150 82

Leukocyte adherence mediated by intercellular adhesion molecule-1 (ICAM-1) binding to leukocyte function-associated antigen (LFA-1) is required for proper inflammatory and immune function. Inhibition of ICAM-1\LFA-1 binding using monoclonal antibodies (mAb) has been shown to be efficacious at inhibiting lymphoma metastasis as well as leukocyte emigration into tissue in a number of inflammatory diseases such as ischemia-reperfusion injury, septic shock and rheumatoid arthritis. In this report, we describe the development and characterization of a small peptide antagonist of ICAM-1-dependent cell aggregation. By using repeated selection of a cyclic nonapeptide phage display library on purified ICAM-1, we identified phage that were competitively eluted with anti-ICAM-1 mAb. The peptide sequences were determined by nucleotide sequencing, and the peptide sequence (C*LLRMRSIC*) (IP01) that occurred most frequently was chosen for further study. Phage expressing this peptide sequence specifically bound ICAM-1 over a range of 5 x 10(6) to 1 x 10(8) phage/microL. A cyclic IP01 peptide, linear IP01 peptide, a cyclic nonapeptide with a scrambled IP01 sequence, and a random, cyclic nonapeptide were synthesized. The cyclic and linear IP01 peptides were able to inhibit ICAM-1-mediated cell aggregation at a concentration of 1 mM, whereas the random and scrambled peptide sequences did not alter aggregation. Cyclic IP01 had a half-maximal inhibitory concentration of approximately 970 microM. Cyclic IP01 did not inhibit cellular aggregation that was dependent on ICAM-2 or ICAM-3. Alanine substitutions in the cyclic IP01 identified at least four amino acids necessary for inhibition of ICAM-1 dependent cell aggregation; leucine 2, leucine 3, methionine 5, and arginine 6. Finally, we showed that cyclic IP01 can inhibit firm adhesion of neutrophils to endothelium, a critical event in inflammatory diseases, in an assay that recapitulates physiologic flow conditions. Homology of IP01 with the primary amino acid sequences of the alpha or beta subunit of LFA-1 was not identified. Thus, we identified a unique molecule that inhibits ICAM-1 dependent cell adhesion, but is not related to the primary sequence of the ICAM-1 ligand LFA-1. Due to the small size and ability to block cell-cell adhesion, IP01 may serve as a useful tool for study of ICAM-1 and LFA-1 biology as well as for the development of small molecule therapeutics.
 ...
PMID:Novel cyclic peptide inhibits intercellular adhesion molecule-1-mediated cell aggregation. 1153 73

Neutrophil infiltration to the tissue, which is one of the important pathogenetic factors in ischemia/reperfusion injury, can be inhibited by glucocorticoids. The purpose of the present study was to clarify the mechanisms by which glucocorticoids inhibit neutrophil infiltration in renal ischemia/reperfusion injury in rats. Pretreatment with dexamethasone significantly attenuated the enhanced neutrophil infiltration and expression of intercellular adhesion molecule-1 induced by renal ischemia/reperfusion. Treatment with nitroxyl anion releaser known as Angeli's salt abolished the beneficial effect of dexamethasone in renal ischemia/reperfusion. Renal dysfunction and tubular damage induced by renal ischemia/reperfusion were not ameliorated by pretreatment with dexamthasone. These results indicate that the attenuation by dexamethasone of neutrophil infiltration and intercellular adhesion molecule-1 expression during renal ischemia/reperfusion may be mediated by the suppressed production of nitroxyl anion. Thus, neutrophil infiltration in renal ischemia/reperfusion injury may be mediated, at least in part, by the enhanced production of nitroxyl anion.
 ...
PMID:Dexamethasone attenuates neutrophil infiltration in the rat kidney in ischemia/reperfusion injury: the possible role of nitroxyl. 1155 19

PR-39 inhibits proteasome-mediated I kappa B alpha degradation and might protect against ischemia-reperfusion injury. We studied PR-39, its truncated form PR-11, and a mutant PR-11AAA, which lacks the ability to prevent I kappa B alpha degradation, in a rat heart ischemia-reperfusion model. After 30 min of ischemia and 24 h of reperfusion, cardiac function, infarct size, neutrophil infiltration, and myeloperoxidase activity were measured. Intramyocardial injection of 10 nmol/kg PR-39 or PR-11 at the time of reperfusion reduced infarct size by 65% and 57%, respectively, which improved blood pressure, left ventricular systolic pressure, and relaxation and contractility (+/-dP/dt) compared with vehicle controls 24 h later. Neutrophil infiltration, myeloperoxidase activity, and the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule 1 were reduced. Thus PR-39 and PR-11 effectively inhibit myocardial ischemia-reperfusion injury in the rat in vivo. This effect is mediated by inhibition of I kappa B alpha degradation and subsequent inhibition of nuclear factor-kappa B-dependent adhesion molecules. The active sequence is located in the first 11 amino acids, suggesting a potential for oligopeptide therapy as an adjunct to revascularization.
 ...
PMID:PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated I kappa B alpha degradation. 1170 30

Prolonged cold ischemia has been suggested as a factor that will exacerbate later graft arterial disease (GAD), a major limiting factor for long-term transplant survival. We therefore examined the effects of cold ischemia on GAD as well as adhesion molecule and cytokine expression in murine cardiac grafts. Mild GAD developed in isografts undergoing 4-hour cold ischemia. Relative to control isografts, cold ischemia induced transiently enhanced endothelial expression of intercellular adhesion molecule-1 (ICAM-1) at 4 hours post-transplant. There was also transiently-augmented gene expression of interleukin (IL)-1beta, IL-6, and transforming growth factor-beta in these cold-ischemic isografts. By 3 days post-transplantation, however, there were no longer any differences between control and cold ischemic isografts. Cold ischemia did not significantly affect the final grade of either parenchymal rejection or GAD in long-term (4 to 12 weeks) major histocompatibility complex (MHC) I- or MHC II-mismatched allografts molecules transplanted without immunosuppression. At early time points after cold ischemia (4 to 24 hours), allografts mismatched for MHC I and/or MHC II showed enhanced expression of ICAM-1 and cytokines comparable to that seen in isografts. By day 7 post-transplant, both control and cold ischemia allografts showed comparable expression of cytokines and adhesion molecules. Although prolonged cold ischemia can initiate mild GAD in isografts by transiently enhancing antigen non-specific inflammatory responses, it does not significantly augment subsequent alloresponses.
 ...
PMID:Cold ischemia induces isograft arteriopathy, but does not augment allograft arteriopathy in non-immunosuppressed hosts. 1189 Dec 4


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>