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)

Plasmalogenase catalyzes the hydrolysis of ethanolamine plasmalogens to long-chain aldehydes and 2-acyl-sn-glycero-3-phosphoethanolamines. During development, plasmalogenase activity parallels myelination. The enzyme is most concentrated within oligodendroglial cells and is absent from myelin. The normal function of plasmalogenase in white matter may be related to its specificity for plasmalogens that contain most of the thromboxane and prostaglandin precursors. Plasmalogenase activities are elevated in demyelinating CNS tissues including canine white matter with lesions due to distemper virus. Elevated plasmalogenase activity precedes cellular invasion and lysosomal activation as indicated by beta-glucuronidase, acid proteinase and neutral proteinase activities. The elevation of plasmalogenase activity was 4.9-fold greater than normal in an early demyelinating lesion caused by the Snyder-Hill strain of distemper virus. Phospholipases acting on phosphatidyl ethanolamine were not activated in this tissue and have activities much lower than plasmalogenase in control tissues. Plasmalogenase activities are also elevated after intracerebral injections of complement-dependent anti-myelin antibody and after ischemia. Plasmalogenase acting on the oligodendrocyte plasma membrane may be responsible for necrosis of the oligodendrocyte that results in demyelination.
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PMID:Plasmalogenase is elevated in early demyelinating lesions. 56 35

Activity of calcium-dependent neutral proteinase and its specific inhibition was investigated in the acutely ischemic myocardium after ligation of the left descending coronary artery in anaesthetized open chest rats. In experiments where the mean arterial blood pressure could be maintained above 70 mm Hg the hearts were quickly removed 5 to 30 min after ligation and homogenized in ice-cold buffer. The activity of the calcium-dependent neutral proteinase and of its endogenous inhibitor were determined in the 10,000 g supernatant of ventricular and septal tissues. Hearts from normal anaesthetized and sham operated animals left on the respirator for 10, 20 and 30 min, were used as controls. Only traces of proteinase activity could be found in the supernatants obtained from normal controls, while in the sham-operated animals the specific activity of the Ca2+-dependent proteinase increased with time, reaching significantly elevated values after 30 min on the respirator. In the ischemic groups enzyme activity also increased with increasing duration of ischemia and was substantially elevated in the ventricular myocardium 20 min after ligation. The increased calcium-dependent proteinase activity was accompanied by significantly reduced activity of its endogenous inhibitor. The concomitant changes in the activities of the myocardial calcium-dependent neutral protease and its endogenous inhibitor suggest that interaction between the enzyme and its inhibitor play a role in the regulation of intracellular calcium-dependent proteolysis.
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PMID:Calcium-dependent proteolysis and its inhibition in the ischemic rat myocardium. 300 92

Experimental spinal cord injury in animals induced by weight drop produces neurological deficit and paralysis. Correlation of the progressive morphological changes in the lesion by both light and electron microscopy with the biochemical alterations revealed ischemia, edema, hemorrhage, tissue necrosis, granular changes in axons, vesicular degeneration of myelin and axonal calcification. The biochemical pathology was that of degradation of axonal (neurofilaments) and myelin proteins (MBP and PLP) with increased activities of proteolytic enzymes and particularly the neutral proteinase. The level of total calcium increased progressively in the lesion to a peak at 8 hrs. and subsequently remained constant thereafter. The capacity of calcium for activating proteinases and lipases and fostering the degradation of axon and myelin proteins as well as the liberation of arachidonic acid required for the synthesis of prostanoids must be relevant. An increased production of prostanoids is indicated by elevation of thromboxane (TxB2), a stable metabolite of TXA2 at 1 hour after injury. The 6-keto-PG1(1)a was also increased but to a lesser extent. We suspect that the activation of arachidonic acid metabolism contributes to post-traumatic vascular injury and the progressive ischemia. These putative roles for calcium in proteolysis and lipolysis, inducing degradation of macromolecules and production of prostanoids which initiate edema, lysolecithin a myelinolytic factor and mitochondrial dysfunction in spinal cord injury are discussed.
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PMID:The multimolecular cascade of spinal cord injury. Studies on prostanoids, calcium, and proteinases. 332 36

Intravital videomicroscopy was used to monitor the migration of leukocytes in rat mesenteric interstitium following exposure of the mesentery to either N-formylmethionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4), platelet-activating factor (PAF), or ischemia-reperfusion (I-R). All inflammatory stimuli resulted in interstitial migration rates that were higher than those measured in unstimulated extravasated leukocytes. The median migration rate of cells stimulated with FMLP was significantly higher than those observed during superfusion with either LTB4 or PAF or following exposure to I-R. The enhanced leukocyte migration rates elicited by I-R were not attenuated by treatment with PAF- and LTB4-receptor antagonists, suggesting that these lipid mediators are not the inflammatory mediators responsible for I-R-induced leukocyte migration. Additional experiments revealed that the rate of leukocyte migration associated with FMLP stimulation was not significantly altered by either inhibitors of neutrophilic elastase and cathepsin G, a monoclonal antibody directed against the leukocyte adhesion glycoprotein CD11/CD18, or by altering interstitial hydration. This in vivo model provides a useful new approach for defining the factors that modulate leukocyte migration within the extravascular compartment.
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PMID:Modulation of leukocyte migration in mesenteric interstitium. 794 4

Plasma endothelin (ET) is increased in association with myocardial infarction. The aim of the present study was to get insight into the mechanisms behind this ischemia-induced increase in plasma ET. Since granulocytes increase ET production in vitro, we examined to what extent inhibition of granulocyte-derived proteases could reduce the increase in plasma ET observed in association with myocardial ischemia. We infused Eglin C, a selective inhibitor of the granulocyte-derived proteases elastase, cathepsin G, and chymotrypsin, in pigs subjected to 90 min left anterior descending coronary artery occlusion followed by 210 min reperfusion (n = 7). Arterial plasma ET increased in an untreated control group (n = 7) from 5.0 +/- 0.6 (mean +/- SEM) fmol . ml-1 before myocardial ischemia to 6.1 +/- 0.6 fmol . ml. at 90 min ischemia and reached a maximum of 6.8 +/- 0.9 fmol . ml-1 at 90 min reperfusion. The increase in plasma ET associated with myocardial ischemia was almost completely abolished in the Eglin C treated group (p = 0.005). Plasma ET in the Eglin C treated animals was 4.7 +/- 0.4, 4.7 +/- 0.4, and 4.6 +/- 0.4 fmol . ml-1 before myocardial ischemia, at 90 min ischemia, and at 90 min reperfusion, respectively. Our study suggests a role for granulocyte-derived proteases in the increase in plasma ET associated with myocardial ischemia. We have shown that the increase in plasma ET associated with myocardial ischemia was reduced by inhibition of granulocyte-derived proteases using the selective protease inhibitor Eglin C.
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PMID:Inhibition of granulocyte-derived proteases reduces the increase in plasma endothelin associated with myocardial ischemia in the pig. 887 78

Heparin has potential use as an antiinflammatory treatment in many lung diseases but its therapeutic use is limited by inherent anticoagulant activity. The anticoagulant nature of heparin can be eliminated by a number of chemical treatments, but often not without loss of other important pharmacological activities. Lyophilization of porcine mucosal heparin under extreme alkaline conditions (pH > or = 13) produces a nonanticoagulant heparin remarkable for the selective loss of only 2-O and 3-O sulfates, leaving 6-O and N-sulfates intact. In contrast to the commonly used nonanticoagulant analog N-desulfated, N-reacetylated heparin, selectively O-desulfated heparin retains potent activity as an inhibitor of the cationic neutrophil proteases human leukocyte elastase and cathepsin G, both in vitro and in vivo. Selectively O-desulfated heparin also inhibits complement lysis of erythrocytes, prevents ischemia-reperfusion injury of the lung, remains a potent antiproliferative treatment for cultured airway smooth muscle and normalizes altered neuronal M2 muscarinic receptor sensitivity and bronchial hyperreactivity after antigen challenge. These retained pharmacologic properties suggest possible use of this new nonanticoagulant heparin for the treatment of a variety of lung disorders.
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PMID:Selective O-desulfation produces nonanticoagulant heparin that retains pharmacological activity in the lung. 922 56

Because neutrophil proteinases such as elastase and cathepsin G are considered to play a major role in inflammatory tissue damage, the microcirculatory effect of the serine proteinase inhibitor (serpin) Lex032 after ischemia/reperfusion (I/R)-induced pancreatitis was investigated. Lex032 inhibits these proteinases by recombinant combination of alpha(1)-antitrypsin and alpha(1)-antichymotrypsin. Twenty-eight anesthetized rats received either Lex032 or NaCl 0.9% as a control solution during baseline conditions or after 1 h of complete reversible ischemia induced by microclip occlusion of the pancreatic arteries. The number of erythrocyte-perfused capillaries (functional capillary density) and the leukocyte adherence in postcapillary venules were assessed by intravital microscopy 45, 90, and 120 min after administration. In the baseline group, Lex032 increased leukocyte adherence compared with the NaCl 0.9% baseline group, without changing any other parameter. I/R without Lex-032 treatment resulted in a 50% reduction in functional capillary density, a 2-fold increase in leukocyte adherence, an increase in interleukin-6 serum concentration, and a significant fall in blood pressure during reperfusion time compared with baseline animals. Treatment with Lex032 in I/R resulted in significant preservation of capillary perfusion, an absence of interleukin-6 increase, and preservation of mean arterial pressure during reperfusion time, without changing the leukocyte adherence, compared with the NaCl 0.9% I/R group. Because of its considerable amelioration of microcirculatory perfusion, Lex032 might be useful in the treatment of pancreatic I/R tissue damage (e.g., cardiac bypass surgery, pancreas transplantation, and hemorrhagic shock) by prevention of capillary perfusion failure.
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PMID:Inhibition of neutrophil proteinases by recombinant serpin Lex032 reduces capillary no-reflow in ischemia/reperfusion-induced acute pancreatitis. 1041 92

Microglia, brain resident macrophages, become activated in brains injured due to trauma, ischemia, or neurodegenerative diseases. In this study, we found that thrombin treatment of microglia induced NO release/inducible nitric-oxide synthase expression, a prominent marker of activation. The effect of thrombin on NO release increased dose-dependently within the range of 5-20 units/ml. In immunoblot analyses, inducible nitric-oxide synthase expression was detected within 9 h after thrombin treatment. This effect of thrombin was significantly reduced by protein kinase C inhibitors, such as Go6976, bisindolylmaleimide, and Ro31-8220. Within 15 min, thrombin activated three subtypes of mitogen-activated protein kinases: extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase/stress-activated protein kinase. Inhibition of the extracellular signal-regulated kinase pathway and p38 reduced the NO release of thrombin-treated microglia. Thrombin also activated nuclear factor kappaB (NF-kappaB) within 5 min, and N-acetyl cysteine, an inhibitor of NF-kappaB, reduced NO release. However, thrombin receptor agonist peptide (an agonist of protease activated receptor-1 (PAR-1)), could not mimic the effect of thrombin, and cathepsin G, a PAR-1 inhibitor, did not reduce the effect of thrombin. These results suggest that thrombin can activate microglia via protein kinase C, mitogen-activated protein kinases, and NF-kappaB but that this occurs independently of PAR-1.
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PMID:Thrombin induces NO release from cultured rat microglia via protein kinase C, mitogen-activated protein kinase, and NF-kappa B. 1089 7

This study tested the hypothesis that classic ischemic preconditioning can cause changes in gene expression patterns in the rabbit heart, assessed by gene array technology. Open-chest rabbits were randomly assigned to sham-operated and ischemically preconditioned groups. The sham-operated group received 5 hours and 20 minutes of no intervention, while the ischemically preconditioned group was subjected to two episodes of preconditioning ischemia (5 minutes each) separated by 5 minutes of reperfusion, followed by an additional 5 hours and 5 minutes of reperfusion. (33)P-labeled cDNA from the sham-operated hearts and the nonischemic and preconditioned areas of the ischemically preconditioned group was hybridized to filters spotted with 18,376 human cDNA clones. Altogether, 35 genes with significantly altered expression patterns were discovered. In the preconditioned area, genes for MAPKAP kinase 3 and cathepsin G were up-regulated. In the nonischemic area, genes for GTP exchange factor, Na(+), K(+)-ATPase, Zn finger protein 35, a representative of the CEA family, cytochrome c oxidase, mitogen-responsive phosphoprotein, and Ran-binding protein were up-regulated. None of the identified genes had been previously reported to be involved in ischemic preconditioning.
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PMID:Gene activity changes in ischemically preconditioned rabbit heart gene: discovery array study. 1197 36

Neutrophil activation to release granules containing proteases and other enzymes is a primary cause of tissue damage during ischemia/reperfusion injury. Because the contribution of specific granule enzymes to this injury remains poorly defined, the role of cathepsin G in renal ischemia/reperfusion injury was tested. Bilateral renal ischemia led to the expiration of 64% of wild-type mice within 4 days of reperfusion, whereas all cathepsin G-deficient mice survived. Serum creatinine increased to similar levels at 24 hours after reperfusion and then decreased to background in both groups of mice. Ischemic kidneys from both groups had similar levels of neutrophil infiltration and of CXCL1, CXCL2, and myeloperoxidase protein 9 hours after reperfusion, but at 24 hours, these acute inflammatory response components were decreased more than 50% in kidneys from cathepsin G-deficient versus wild-type mice. Ischemic kidneys from surviving wild-type mice had severe tubular necrosis and tubular cell apoptosis 24 hours after reperfusion with subsequent development of fibrosis 30 days later. In contrast, ischemic kidneys from cathepsin G-deficient mice had a 70% decrease in tubular cell apoptosis with little detectable collagen deposition. These data identify cathepsin G as a critical component sustaining neutrophil-mediated acute tissue pathology and subsequent fibrosis after renal ischemia/reperfusion injury.
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PMID:Cathepsin g is required for sustained inflammation and tissue injury after reperfusion of ischemic kidneys. 1732 78


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