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)

Tumor necrosis factor-alpha (TNF-alpha) has two forms with apparently different biological activities: a membrane-associated form and a soluble form. TNF-alpha-converting enzyme (TACE) mediates a cleavage of membrane-associated TNF-alpha to induce its bioactive soluble form. We hypothesized that inhibition of TACE might prevent TNF-alpha-induced tissue injury while preserving the benefits of TNF-alpha. In this study, we evaluated the role of TACE in acute inflammation using an inhibitor of the enzyme in a rat model of lung transplantation. Inbred Lewis rats underwent left lung isotransplantation, and the donor lungs were kept in Euro-Collins solution with or without the inhibitor. After 6 hours of ischemia, the left lung was transplanted into the recipient rat and reperfused for 4 hours. Inhibition of TACE significantly attenuated endothelial and alveolar septal damage, as assessed by radiolabeled albumin leakage after transplantation. The inhibition also attenuated neutrophil accumulation in the alveolar space and other histopathologic findings, including intercellular adhesion molecule-1 expression. In addition, significantly lower levels of monocyte chemotactic protein-1, cytokine-induced neutrophil chemoattractant-1, high mobility group box-1, and soluble epithelial cadherin and decreased neutrophil elastase activity were observed in bronchoalveolar lavage fluid from the rats treated with the inhibitor. We conclude that TACE mediates a critical step in the development of post-transplantation lung injury.
 ...
PMID:Importance of tumor necrosis factor-alpha cleavage process in post-transplantation lung injury in rats. 1533 31

Neutrophils play an important role in ischemia-reperfusion injury. The neutrophil elastase not only causes tissue damage, but also mediates neutrophil priming. In the present study, we use a rabbit model of hepatoenteric ischemia-reperfusion to test the hypothesis that neutrophil elastase inhibition ameliorates an ischemia-reperfusion injury by attenuating neutrophil priming and suppressing enzymatic activity. Twenty-four Japanese white rabbits underwent 30 min of supraceliac aortic cross-clamping and 180 min of reperfusion under isoflurane anesthesia. The rabbits randomly received the neutrophil elastase inhibitor, sivelestat (n = 10), or saline (n = 14). Neutrophil priming was then assayed with luminol-dependent neutrophil chemiluminescence. Hepatic, intestinal, renal, and pulmonary damages were assessed with serum transaminase, lactate dehydrogenase concentrations, urinary N-acetyl glucosaminidase activity, and protein concentration in post mortem bronchoalveolar lavage fluid. We discovered that neutrophil elastase inhibition suppressed plasma neutrophil elastase, and that lipid peroxide concentrations increased after reperfusion. It improved ischemia-reperfusion injuries in the liver, intestine, kidney, and lung. Furthermore, inhibition of neutrophil elastase with sivelestat significantly attenuated post-reperfusion neutrophil priming. The results of this study demonstrate that neutrophil elastase inhibition could effectively attenuate an ischemia-reperfusion injury caused by supraceliac aortic cross-clamping, most likely from the attenuation of neutrophil priming.
 ...
PMID:Sivelestat, a neutrophil elastase inhibitor, attenuates neutrophil priming after hepatoenteric ischemia in rabbits. 1566 31

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.
 ...
PMID:Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model. 1620 20

Hepatocyte growth factor (HGF) is a plasminogen-like protein with an alpha chain linked to a trypsin-like beta chain without peptidase activity. The interaction of HGF with c-met, a receptor tyrosine kinase expressed by many cells, is important in cell growth, migration, and formation of endothelial and epithelial tubes. Stimulation of c-met requires two-chain, disulfide-linked HGF. Portions of an alpha chain containing an N-terminal segment and four kringle domains (NK4) antagonize HGF activity. Until now, no physiological pathway for generating NK4 was known. Here we show that chymases, which are chymotryptic peptidases secreted by mast cells, hydrolyze HGF, thereby abolishing scatter factor activity while generating an NK4-like antagonist of HGF scatter factor activity. Thus, chymase interferes with HGF directly by destroying active protein and indirectly by generating an antagonist. The site of hydrolysis, Leu480, lies in the alpha chain on the N-terminal side of the cysteine linking the alpha and beta chains. This site appears to be specific for HGF because chymase does not hydrolyze other plasminogen-like proteins, such as macrophage-stimulating protein and plasminogen itself. Mast cell/neutrophil cathepsin G and neutrophil elastase generate similar fragments of HGF by cleaving near the chymase site. Mast cell and neutrophil peptidases are secreted during tissue injury, infection, ischemia, and allergic inflammation, where they may oppose HGF effects on epithelial repair. Thus, HGF possesses an "inactivation segment" that serves as an Achilles' heel attacked by inflammatory proteases. This work reveals a potential physiological pathway for inactivation of HGF and generation of NK4-like antagonists.
 ...
PMID:Mast cell and neutrophil peptidases attack an inactivation segment in hepatocyte growth factor to generate NK4-like antagonists. 1630 61

Renal ischemia-reperfusion (I/R) injury is a significant problem in renal transplantation. Neutrophils play an important role in renal I/R injury. Several reports have demonstrated that neutrophil elastase derived from the activated neutrophils might play an important role in this injury. We investigated the effect of a neutrophil elastase inhibitor in renal I/R injury. Male Lewis rats (270-320 g) were used in the model. The right kidney was harvested and the left renal artery and vein were clamped at laparotomy. The kidney was reperfused after 90 minutes of ischemia. Neutrophil elastase inhibitor (ONO-5046: 30 mg/kg) was delivered intravenously before ischemia and after reperfusion to prevent neutrophil activation. In the nontreatment I/R group, no hosts survived 4 days. However, after treatment with neutrophil elastase inhibitor, 3 of 10 rats in the I/R group, survived more than 7 days. These results demonstrated that treatment with neutrophil elastase inhibitor ameliorated renal I/R injury.
 ...
PMID:Benefical effect of neutrophil elastase inhibitor on renal warm ischemia-reperfusion injury in the rat. 1698 42

Neutrophil elastase, which enhances intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells, plays an important role in ischemia/reperfusion injury. Here, we investigated signal transduction of ICAM-1 expression in endothelial cells stimulated by neutrophil elastase. Pretreatment of animals with the neutrophil elastase inhibitor, ONO-5046.Na significantly decreased the number of neutrophils or Mac-1(+) (CD11b/CD18) cells in ischemic liver lobes after reperfusion. ICAM-1 expression in the rat endothelial cell line (WK-5) was significantly upregulated after stimulation with neutrophil elastase, but this reaction was inhibited by the neutrophil elastase inhibitor ONO-5046.Na. ICAM-1 mRNA expression, which is induced by neutrophil elastase in a dose-dependent manner, was repressed by the alpha1-protease inhibitor. ICAM-1 expression, stimulated by neutrophil elastase, was partially reduced by a diacylglycerol kinase inhibitor and protein kinase C inhibitor, but was completely inhibited by a phospholipase C inhibitor, cytosolic Ca(2+) chelator, calmodulin antagonist, and nuclear transcription factor kappa B inhibitor. Binding of (125)I-neutrophil elastase to WK-5 cells was competitively inhibited by the addition of unlabeled neutrophil elastase. The neutrophil elastase inhibitor significantly reduces ICAM-1 expression and Mac-1(+) cell accumulation in ischemic liver lobes after reperfusion. Neutrophil elastase stimulates ICAM-1 expression in endothelial cells by intracellular signal transduction via activation of diacylglycerol kinase, protein kinase C, phospholipase C, Ca(2+)-calmodulin, and nuclear transcription factor kappa B.
 ...
PMID:ICAM-1 signal transduction in cells stimulated with neutrophil elastase. 1702 74

In the present study, we evaluated the effect of neutrophil elastase inhibitor, sivelestat sodium hydrate on ischemia-reperfusion injury in the rat bladder. Rat abdominal aorta was clamping with a small clip to induce ischemia-reperfusion injury in the bladder. Eight-week-old male Sprague Dawley rats were divided into four groups; sham-operated control rats, 30 min ischemia-60 min reperfusion (IR) rats, and IR rats treated with 15 or 60 mg/kg of sivelestat sodium hydrate. Sixty minutes prior to induction of ischemia, sivelestat sodium hydrate was administrated intraperitoneally. Real-time monitoring of blood flow and nitric oxide (NO) release were measured simultaneously with a laser Doppler flowmeter and an NO-selective electrode, respectively. The NO2-NO3 and malonaldehyde (MDA) concentrations were measured in the experimental urinary bladders. Clamping of the abdominal aorta, blood flow was rapidly decreased and NO release was gradually increased. After removing the clip, blood flow was rapidly increased and NO release was gradually returned to the basal level. These movements of blood flow and NO release were inhibited by treatment with sivelestat sodium hydrate in a dose-dependent manner. Both NO2-NO3 and MDA concentrations in the bladder were increased by induction of IR, and NO2-NO3 and MDA concentrations were decreased by treatment with high dose of sivelestat sodium hydrate significantly. Our data indicated that sivelestat sodium hydrate could inhibit increasing NO2-NO3 and MDA concentrations by IR, and it has potentiality protective effects on IR injury in the rat urinary bladder.
 ...
PMID:Neutrophil elastase inhibitor, sivelestat sodium hydrate prevents ischemia-reperfusion injury in the rat bladder. 1816 24

The effect of Sivelestat, a neutrophil elastase inhibitor, on hepatic ischemia-reperfusion injury was examined in a pig hepatectomy model. An internal jugular vein-splenic vein bypass was prepared in male pigs and about 40% hepatic resection (left lobe) was performed under 15-min liver ischemia and 5-min intermittent reperfusion. Six animals received Sivelestat (10 mg/kg/h) intravenously and six control animals received physiological saline (10 mg/kg/h) from commencement of laparotomy. Hemodynamics, blood chemistry, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), lactic acid, hyaluronic acid, nitrite/nitrate (NOS), and tumor necrosis factor-alpha (TNF-alpha) were compared between the groups. The effects of Sivelestat on NOS generation and expression of iNOS mRNA and TNF-alpha mRNA were also assessed in J774 cells. Expression of TNF-alpha mRNA in hepatic tissues was examined using RT-PCR. The blood pressure of control animals was significantly lower immediately and 3 h after ischemia-reperfusion, compared with that at commencement of laparotomy, whereas there was no decrease of blood pressure in animals administered Sivelestat. Serum AST (P=0.0045), NOS (P=0.0098), and TNF-alpha (P=0.041) levels were significantly lower 3 h after hepatectomy in animals receiving Sivelestat. Sivelestat inhibited NOS production in J774 cells, but did not inhibit expression of iNOS mRNA or TNF-alpha mRNA. In hepatic tissues, Sivelestat showed a greater tendency to inhibit expression of TNF-alpha mRNA and fewer TUNEL-positive cells were present in the hepatic sinusoidal endothelium after Sivelestat treatment, although these differences were not statistically significant. We conclude that Sivelestat inhibits production of TNF-alpha and NO by inhibiting neutrophil elastase, and thus reduces hepatic injury and stabilizes hemodynamics after ischemia-reperfusion.
 ...
PMID:Protective effect of Sivelestat in a porcine hepatectomy model prepared using an intermittent Pringle method. 1837 31

Inflammatory responses have been known to contribute to the development of neuronal damage after brain ischemia in experimental animals. Also, neutrophil elastase activity in the plasma has been elevated in the patients with acute cerebral infarction. In order to clarify whether neutrophil elastase distributes into the brain parenchyma and exacerbates neuronal damage following ischemia, we examined the effects of specific neutrophil elastase inhibitor, ONO-5046, on hippocampal CA1 neuronal death in relation to neutrophil elastase activity in the plasma and its distribution in the brain and to caspase-3/7 activity. ONO-5046 (5 and 10 mg/kg) or saline (control group) was administrated after 8 min of forebrain ischemia in rats. Ratio of surviving neurons (median, [range]) in hippocampal CA1 seven days after ischemia was significantly higher in the ONO-5046 5 mg/kg (31% [12-57%]), and 10 mg/kg groups (69% [39-76%]) than in the control group (3.2% [0-10%]). Plasma neutrophil elastase activity in the ONO-5046 10 mg/kg group was significantly lower than in the control group (14 [11-25] vs. 41 [35-68] nmol/ml). Neutrophil elastase distributed in the extracellular space in the hippocampal CA1 neuronal layer in the control group, while, in the ONO-5046 10 mg/kg group, trace of neutrophil elastase was detected only in the endothelium. Caspase-3/7 activity was elevated after ischemia over 8 h in the control group, while, in the ONO-5046 10 mg/kg group, no elevation was observed. The results suggest that neutrophil elastase may contribute to neuronal death in hippocampal CA1 following forebrain ischemia and that neutrophil elastase inhibitor attenuates neuronal death.
 ...
PMID:Neutrophil elastase inhibitor attenuates hippocampal neuronal damage after transient forebrain ischemia in rats. 1916 36

Sivelestat, a neutrophil elastase inhibitor, has been shown to attenuate pulmonary injury during ischemia and reperfusion by improving microcirculation and may be effective as a cardioprotective agent. Isolated rat hearts were Langendorff-perfused (constant pressure, 75 mmHg) with oxygenated Krebs-Henseleit bicarbonate buffer (KHB). The optimal sivelestat concentration at 19 micromol/l was revealed because left ventricular developed pressure (LVDP) recovery in 19 micromol/l sivelestat was highest among 0.19, 1.9, 19, 190, and 1900 micromol/l sivelestat (26+/-10, 33+/-7, 56+/-5*, 35+/-2, and 15+/-5%, respectively; *P<0.01). In order to examine the optimal administration timing, sivelestat was administered at pre- and post-ischemic phases. LVDP recovery and troponin-T were observed in pre-, post-ischemic sivelestat groups and control. After 60 min-reperfusion, LVDP recoveries were 42+/-10*, 45+/-19*, and 14+/-5%, respectively (*P<0.01 compared to control), and troponin-T values were 4+/-1, 2+/-1**, and 8+/-2, respectively (**P<0.05 compared to control). Acetylcholine-induced increase in coronary flow was also investigated to examine the sivelestat's cardioprotective mechanism. Ischemia-reperfusion (I/R) impaired the acetylcholine-induced increase in coronary flow (maximal changes: sham, 125+/-11%; I/R, 98+/-3; P<0.01) and this impairment was attenuated by sivelestat-perfusion at reperfusion (maximal change: 112+/-7%; P<0.05 vs. I/R). Sivelestat attenuates coronary endothelial ischemia-reperfusion injury and improves myocardial protection even when administered at the reperfusion period. This suggests a role for sivelestat in the preservation of coronary endothelial function enhancing myocardial protection.
 ...
PMID:Sivelestat reduces myocardial ischemia and reperfusion injury in rat hearts even when administered after onset of myocardial ischemia. 1927 53


<< Previous 1 2 3 4 5 Next >>