Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Pressure ulcers are a significant healthcare concern, especially for elderly populations. Our work served to ameliorate the chronicity of these ulcers by addressing ischemia-reperfusion injury mediated by neutrophils and the concomitant loss of vasculature in these wounds. To this end, chitosan scaffolds loaded with basic fibroblast growth factor (bFGF) contained in gelatin microparticles were developed and tested for clinical relevance in an aged mouse model. Pressure ulcers were induced in aged mice, and efficacy of treatment was assessed. On days 3 and 7, both chitosan and chitosan-bFGF scaffolds significantly accelerated wound closure compared to gauze control. By day 10, all wounds achieved similar closure. Delivery and angiogenic function of bFGF was verified through ELISA and histology. Elevated neutrophil levels were observed in chitosan and chitosan-bFGF groups. Since neutrophil elastase contributes to the proteolytic environments of pressure ulcers, the effect of chitosan on elastase was assessed. In vitro, chitosan inhibited elastase activity. In vivo, elastase protein levels in wounds were reduced with chitosan-bFGF scaffolds by day 10. These results suggest that chitosan is an effective material for growth factor delivery and can help to heal chronic ulcers. Collectively, our data show that chitosan-bFGF scaffolds are effective in accelerating wound closure of pressure ulcers in aged animals.
 ...
PMID:Accelerated wound closure of pressure ulcers in aged mice by chitosan scaffolds with and without bFGF. 1934 20

Neutrophils are considered crucial effector cells in the pathophysiology of organ ischemia/reperfusion injury (IRI). Although neutrophil elastase (NE) accounts for a substantial portion of the neutrophil activity, the function of NE in liver IRI remains unclear. This study focuses on the role of NE in the mechanism of liver IRI. Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 minutes, and this was followed by 6 to 24 hours of reperfusion. Mice were treated with neutrophil elastase inhibitor (NEI; 2 mg/kg per os) at 60 minutes prior to the ischemia insult. NEI treatment significantly reduced serum alanine aminotransferase levels in comparison with controls. Histological examination of liver sections revealed that unlike in controls, NEI treatment ameliorated hepatocellular damage and decreased local neutrophil infiltration, as assessed by myeloperoxidase assay, naphthol AS-D chloroacetate esterase stains, and immunohistochemistry (anti-Ly-6G). The expression of pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin 6) and chemokines [chemokine (C-X-C motif) ligand 1 (CXCL-1), CXCL-2, and CXCL-10] was significantly reduced in the NEI treatment group, along with diminished apoptosis, according to terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and caspase-3 activity. In addition, toll-like receptor 4 (TLR4) expression was diminished in NEI-pretreated livers, and this implies a putative role of NE in the TLR4 signal transduction pathway. Thus, targeting NE represents a useful approach for preventing liver IRI and hence expanding the organ donor pool and improving the overall success of liver transplantation. Liver Transpl 15:939-947, 2009. (c) 2009 AASLD.
 ...
PMID:The inhibition of neutrophil elastase ameliorates mouse liver damage due to ischemia and reperfusion. 1964 32

BACKGROUND.: A neutrophil elastase (NE) inhibitor, Sivelestat, has been approved for the treatment of acute lung injury associated with systemic inflammation in humans. Some reports have also shown its protective effects in liver inflammatory states. We have recently documented the importance of NE in the pathophysiology of liver ischemia/reperfusion injury, a local Ag-independent inflammation response. This study was designed to explore putative cytoprotective functions of clinically available Sivelestat in liver ischemia/reperfusion injury. METHODS.: Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6 or 24 hr of reperfusion. The mice were given Sivelestat (100 mg/kg, subcutaneous) at 10 min before ischemia, 10 min before reperfusion, and at 1 and 3 hr of reperfusion thereafter. RESULTS.: Sivelestat treatment significantly reduced serum alanine aminotransferase levels and NE activity, when compared with controls. Histological liver examination has revealed that unlike in controls, Sivelestat ameliorated the hepatocellular damage and decreased local neutrophil activity and infiltration. The expression of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), chemokines (CXCL-1, CXCL-2, and CXCL-10), and toll-like receptor 4 was significantly reduced in the treatment group, along with diminished apoptosis through caspase-3 pathway. Moreover, in vitro studies confirmed downregulation of proinflammatory cytokine and chemokine programs in mouse macrophage cell cultures, along with depression of innate toll-like receptor 4 signaling. CONCLUSION.: Sivelestat-mediated NE inhibition may represent an effective therapeutic option in liver transplantation and other inflammation disease states.
 ...
PMID:The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury. 2068 30

Release of neutrophil elastase is one of the harmful inflammatory reactions in acute cerebral ischemia. Therefore, inhibition of elastase released from neutrophils could be a useful strategy for the treatment of acute stroke. To evaluate this hypothesis, the effect of sivelestat, a selective neutrophil elastase inhibitor was examined in a mouse model of focal ischemia. The results obtained indicate that sivelestat reduced brain edema and vascular permeability, and subsequently improved the neurological deficit in an acute focal ischemia. The architecture of microvessels was analyzed by identifying vascular endothelial cells, which were prelabeled by injecting fluorescein-labeled Griffonia simplicifolia lectin I-isolectin B4 into a tail vein. Most of the microvessels in the infarcted area were structurally destroyed in the control group. In sharp contrast, microvessels in the boundary zone were well maintained in the sivelestat-treated group. Moreover, the expression of angiopoietin-1 was elevated at the ischemic margin in the sivelestat-treated group. Furthermore, the neutrophil elastase inhibitor rescued human brain microvascular endothelial cells in culture from neutrophil elastase-induced damage. These results suggest that neutrophil elastase inhibition could protect blood-brain barrier function in acute cerebral ischemia by augmentation of angiopoietin-1 expression and survival of endothelial cells.
 ...
PMID:Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema. 2048 41

Sequestration of activated PMN and enrichment in tissues play a key role in tissue damage during septicaemia and after ischemia/reperfusion. Since polymorphonuclear neutrophilic granulocytes (PMN) of term neonates show various functional differences compared to PMN in adults (decreased chemotaxis, decreased intracellular killing, decreased adhesion) we studied the influence of interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) on the reduction of deformability of PMN in neonates and adults. The following phosphodiesterase (PDE)-inhibitors were applied to ameliorate the reduction in deformability when the PMN were stimulated with fMLP or IL-8: Enoximone, Milrinone (PDE-III-inhibitors), Pentoxifylline (PTX) and Piclamilast (PDE-IV-inhibitors). The micropipette technique and the cell transit analyzer (CTA) were used and compared. Aspiration times into micropipettes with an internal diameter of 5 microm, transit times through 8 microm filter pores and neutrophil elastase concentrations were determined. Despite of the functional differences of PMN in neonates compared to adults the significant decrease of deformability of PMN activated with cytokines compared to passive PMN was not different in both groups. The neutrophil elastase concentrations reflect the activation of the PMN: highest concentrations during activation, decreased concentrations due to PDE-inhibitors, and PMN in a passive state. The neutrophil elastase concentrations were not different from PMN of neonates and adults. These PDE-inhibitors significantly increased the deformability of activated PMN but significant differences between the deformability of PMN in neonates and adults were not found. Despite the functional differences of PMN in neonates PDE-III/IV-inhibitors lead to similar improvement of mechanical properties of activated PMN in neonates and adults. These drugs may ameliorate impaired microcirculation also in neonates during inflammation.
 ...
PMID:Effects of phosphodiesterase (III/IV)-inhibitors and cytokines on mechanical properties of neutrophilic granulocytes in neonates and adults. 2067 13

In renal transplantation, ischemia-reperfusion (I/R) injury is a major cause of renal dysfunction. Activated neutrophils are reported to be closely involved in I/R injury after renal transplantation. Neutrophil elastase, a protease released from activated neutrophils, damages tubular endothelial cells. We investigated the beneficial effect of neutrophil elastase inhibitor (ONO-5046.Na) on renal I/R injury in rats. The study was conducted using 10 male Lewis rats (270-320 g) that were intravenously administered ONO-5046.Na (30 mg/kg before ischemia and after reperfusion) (group A) and control rats (group B) in a 90-min renal warm I/R injury model. Neutrophil elastase expression was analyzed using immunohistochemical staining, and the degree of renal dysfunction was evaluated using H&E staining and blood biochemistry. Neutrophil elastase was detected in tubular endothelial cells. The necrotic area extended to and encompassed nearly all the ischemic kidney within 12 h after reperfusion. The necrotic area and the grade of neutrophil elastase staining were significantly reduced in group A compared to group B. Significant differences in blood urea nitrogen and serum creatinine levels were observed. Survival rates over a 14-day period were examined. No rats survived for more than 4 days in group B. However, 2 of the 10 rats (20%) in group A survived for a 14-day period. To conclude, ONO-5046.Na inhibits neutrophil elastase and reduces acute tubular necrosis. Thus, it is a potent therapeutic agent for the control of renal I/R injury in renal transplantation.
 ...
PMID:The effect of neutrophil elastase inhibitor on acute tubular necrosis after renal ischemia-reperfusion injury. 2147 37


<< Previous 1 2 3 4 5 6 Next >>