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)

We investigated the role of polymorphonuclear neutrophil (PMN) proteinases, elastase, and gelatinase B in rat models of acute lung injury. Three groups of rats were studied 6 hours after unilateral instillation of hydrochloric acid (HCl; 0.1 N), lipopolysaccharide (LPS) (4 microg), or saline. The results demonstrated that HCl-induced lung injury, as compared with LPS-induced lung injury, was associated with an increase in permeability (wet/dry weight ratio and proteins in bronchoalveolar lavage fluid). In contrast, there was similar PMN recruitment (in bronchoalveolar lavage fluid and myeloperoxidase activity in lung homogenates) and similar proteinase exocytosis (residual alveolar PMN content of elastase and gelatinase B) in both types of lung injury. In situ zymography, evaluating interstitial protease/inhibitor balance, demonstrated a decrease in gelatinolytic activity in both HCl- and LPS-injured lungs compared with normal lung. The increase in interleukin 6 concentration in lung homogenates, which is observed after both injuries compared with saline-instilled animals, could be involved in up-regulation of tissue inhibitor of matrix metalloproteinase-1, shown by immunocytochemistry to participate in antiproteinase excess. Neither inhibition of alveolar neutrophil influx using a leukocyte elastase inhibitor (EPI-hNE-4) nor inhibition of gelatinase activities by recombinant adenovirus for the human tissue inhibitor of matrix metalloproteinase 1 gene transfer decreased lung edema in HCl-induced injury. These data suggest that PMN proteinases do not contribute to HCl-induced acute lung injury in rats.
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PMID:Neutrophil proteinases in hydrochloric acid- and endotoxin-induced acute lung injury: evaluation of interstitial protease activity by in situ zymography. 1185 May 27

Excessive accumulation of active neutrophil elastase (NE) in pulmonary fluids and tissues of patients with cystic fibrosis (CF) is thought to act on the lungs, compromising their structure and function. The aim of this study was to investigate the in vitro and in vivo protective effect of a new, rapidly acting, potent (Ki = 5.45 x 10(-12) M and Kon = 8 x 10(6) M(-1) s(-1)) and specific human NE inhibitor, EPI-HNE-4, engineered from the Kunitz domain. The results demonstrated that this inhibitor was able to (i) effectively inhibit in vitro the high levels of active NE present in a medium as complex as sputum from children with CF, with a measured IC(50) equal or close to the calculated IC(50) in 60% of cases, and (ii) almost completely block (91%) the N-formyl-methionine-leucine-phenylalanine-induced migration of purified human neutrophils across a Matrigel basement membrane. Intratracheal administration (250, 175, or 100 microg per rat) of the inhibitor 5 min before instillation of pure human NE (HNE) (150 microg per rat) to rats induced effective, dose-dependent protection of the lungs, 4 h later, from hemorrhage, serum albumin leakage, residual active NE, and discrete neutrophil influx in air spaces induced by instillation of pure HNE. Intravenous administration (3 mg per rat) of EPI-HNE-4, 15 min before instillation of the soluble fraction of pooled sputum (delivering 120 microg of active NE per rat) from children with CF, effectively reduced (64%), 4 h later, the massive neutrophil influx induced by sputum instillation. Overall, these data strongly suggest that associated aerosol and systemic administration of EPI-HNE-4 would be beneficial in the treatment of CF.
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PMID:Protection against acute lung injury by intravenous or intratracheal pretreatment with EPI-HNE-4, a new potent neutrophil elastase inhibitor. 1186 32

The purpose of this study was to define nebulization conditions providing delivery of aerosols of EPI-hNE4, an inhibitor of human neutrophil elastase (HNE). EPI-hNE4 was nebulized with Pari LC Star and tested at three concentrations (2.5, 5, and 10 mg/mL). The inhaled mass was measured over 15 min. Particle size distribution was measured by cascade impaction. The effect was also tested of mixing EPI-hNE4 with a (99m)Tc human serum albumin (HSA) tracer on the aerodynamic properties of the aerosol. The inhibitory activity of EPI-hNE4 after nebulization was assessed on purified HNE. The inhaled mass was 32.3 +/- 3.5% (mean +/- SD) after 10 min and 44.2 +/- 3.8% (mean +/- SD) after 15 min. Mass median aerodynamic diameter ranged between 1.2 and 1.8 microm. The (99m)Tc HSA EPI-hNE4 aerosol was similar in terms of particle size distribution (y = 1.0338x - 0.003, r = 0.83). (99m)Tc activity was predictive of EPI-hNE4 mass distribution (y = 1.0278x - 1.6991, r = 0.89). The inhibitory capacity of aerosolized samples remained unchanged after up to 10 min of nebulization. EPI-hNE4 can be nebulized efficiently without decrease in its activity. Mixing this inhibitor with (99m)Tc HSA should allow quantification of its deposition in CF patients.
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PMID:Characteristics of EPI-hNE4 aerosol: a new elastase inhibitor for treatment of cystic fibrosis. 1282 6

Chronic obstructive pulmonary disease (COPD) is a common, smoking-related, severe respiratory condition characterised by progressive, irreversible airflow limitation. Current treatment of COPD is symptomatic, with no drugs capable of halting the relentless progression of airflow obstruction. Better understanding of the airway inflammation, oxidative stress and alveolar destruction that characterise COPD has delineated new disease targets, with consequent identification of novel compounds with therapeutic potential. These new drugs include aids to smoking cessation (e.g. bupropion) and improvements to existing therapies, for example long-acting rather than short-acting bronchodilators, as well as combination therapy. New antiproteases include acyl-enzyme and transition state inhibitors of neutrophil elastase (e.g. sivelestat and ONO-6818), matrix metalloprotease inhibitors (e.g. batimastat), cathepsin inhibitors and peptide protease inhibitors (e.g. DX-890 [EPI-HNE-4] and trappin-2). New antioxidants include superoxide dismutase mimetics (e.g. AEOL-10113) and spin trap compounds (e.g. N-tert-butyl-alpha-phenylnitrone). New anti-inflammatory interventions include phosphodiesterase-4 inhibitors (e.g. cilomilast), inhibitors of tumour necrosis factor-alpha (e.g. humanised monoclonal antibodies), adenosine A(2a) receptor agonists (e.g. CGS-21680), adhesion molecule inhibitors (e.g. bimosiamose [TBC1269]), inhibitors of nuclear factor-kappaB (e.g. the naturally occurring compounds hypoestoxide and (-)-epigallocatechin-3-gallate) and activators of histone deacetylase (e.g. theophylline). There are also selective inhibitors of specific extracellular mediators such as chemokines (e.g. CXCR2 and CCR2 antagonists) and leukotriene B(4) (e.g. SB201146), and of intracellular signal transduction molecules such as p38 mitogen activated protein kinase (e.g. RWJ67657) and phosphoinositide 3-kinase. Retinoids may be one of the few potential treatments capable of reversing alveolar destruction in COPD, and a number of compounds are in clinical trial (e.g. all-trans-retinoic acid). Talniflumate (MSI-1995), an inhibitor of human calcium-activated chloride channels, has been developed to treat mucous hypersecretion. In addition, the purinoceptor P2Y(2) receptor agonist diquafosol (INS365) is undergoing clinical trials to increase mucus clearance. The challenge to transferral of these new compounds from preclinical research to disease management is the design of effective clinical trials. The current scarcity of well characterised surrogate markers predicts that long-term studies in large numbers of patients will be needed to monitor changes in disease progression.
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PMID:Therapy for chronic obstructive pulmonary disease in the 21st century. 1296 14

Persistence of alveolar neutrophil influx and activation may enhance the fibrotic process after acute lung injury. On the other hand, elastase has an antimicrobial activity and could participate in neutrophil migration, both events being critically important in host defense, explaining the controversial issue of therapeutic elastase inhibition in the setting of acute lung injury. We assessed the effect of a neutrophil elastase inhibitor, EPI-hNE-4, in single (bleomycin, 1.2 mg/rat intratracheally) and repeated (bleomycin, 1.2 mg/rat plus endotoxin and 1 mg/kg intratracheally 24 h later) lung injuries to assess the role of neutrophil in fibrosis. Subsequently, the effect of EPI-hNE-4 on bacterial clearance was evaluated during Pseudomonas aeruginosa-induced pneumonia. In the single injury model, despite a dramatic reduction of alveolar neutrophil influx with EPI-hNE-4 treatment, no significant inhibition of the decrease in respiratory system compliance, an index of lung fibrosis, was demonstrated at day 14. In the repeated injury model, EPI-hNE-4 treatment afforded a significant protective effect on compliance and alveolar inflammation at day 14. During bacterial pneumonia, EPI-hNE4 did not modify alveolar neutrophil recruitment or bacterial clearance from bronchoalveolar lavage fluid and lung homogenate. In conclusion, EPI-hNE-4, a specific inhibitor of leukocyte elastase, afforded a partial protective effect on the respiratory system compliance during repeated lung injuries, and had no detrimental effect during a gram-negative bacterial pneumonia.
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PMID:Beneficial effect of an inhibitor of leukocyte elastase (EPI-hNE-4) in presence of repeated lung injuries. 1525 85

EPI-hNE4 (depelstat) is a potent inhibitor of human neutrophil elastase derived from human inter-alpha-trypsin inhibitor and designed to control the excess proteolytic activity in the sputum of cystic fibrosis patients. We analyzed its resistance to the proteolysis it is likely to encounter at inflammatory sites in vivo. EPI-hNE4 resisted hydrolysis by neutrophil matrix metalloproteases (MMPs) and serine proteases that are released from activated neutrophils in inflammatory lung secretions, including MMP-8 and MMP-9, and the elastase-related protease 3 and cathepsin G. It also resisted degradation by epithelial lung cell MMP-7 but was broken down by the Pseudomonas aeruginosa metalloelastase pseudolysin, when used in a purified system, but not when this protease competed with equimolar amounts of neutrophil elastase. We also investigated the inhibitory properties of EPI-hNE4 at the surface of purified blood neutrophils and in the sputum of cystic fibrosis patients where neutrophil elastase is in both a soluble and a gel phase. The elastase at the neutrophil surface was fully inhibited by EPI-hNE4 and formed soluble complexes. The elastase in cystic fibrosis sputum supernatants was inhibited by stoichiometric amounts of EPI-hNE4, allowing titration of the protease. But the percentage of inhibition in whole sputum homogenates varied from 50 to 100%, depending on the sample tested. EPI-hNE4 was rapidly cleaved by the digestive protease pepsin in vitro. Therefore, EPI-hNE4 seems to be an elastase inhibitor suitable for use in aerosols to treat patients with cystic fibrosis.
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PMID:EPI-hNE4, a proteolysis-resistant inhibitor of human neutrophil elastase and potential anti-inflammatory drug for treating cystic fibrosis. 1662 47

The amiloride-sensitive epithelial sodium channel (ENaC) constitutes a limiting step in sodium reabsorption across distal airway epithelium and controlling mucociliary clearance. ENaC is activated by serine proteases secreted in the extracellular milieu. In cystic fibrosis lungs, high concentrations of secreted neutrophil elastase (NE) are observed. hNE could activate ENaC and contribute to further decreased mucociliary clearance. The aims of this study were (i) to test the ability of an engineered human neutrophil elastase inhibitor (EPI-hNE4) to specifically inhibit the elastase activation of ENaC-mediated amiloride-sensitive currents (I(Na)) and (ii) to examine the effect of elastase on cell surface expression of ENaC and its cleavage pattern (exogenous proteolysis). Oocytes were exposed to hNE (10-100 microg/ml) and/or trypsin (10 microg/ml) for 2-5 min in the presence or absence of EPI-hNE4 (0.7 microm). hNE activated I(Na) 3.6-fold (p < 0.001) relative to non-treated hENaC-injected oocytes. EPI-hNE4 fully inhibited hNE-activated I(Na) but had no effect on trypsin- or prostasin-activated I(Na). The co-activation of I(Na) by hNE and trypsin was not additive. Biotinylation experiments revealed that cell surface gamma ENaC (but not alpha or beta ENaC) exposed to hNE for 2 min was cleaved (as a 67-kDa fragment) and correlated with increased I(Na). The elastase-induced exogenous proteolysis pattern is distinct from the endogenous proteolysis pattern induced upon preferential assembly, suggesting a causal relationship between gamma ENaC cleavage and ENaC activation, taking place at the plasma membrane.
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PMID:A novel neutrophil elastase inhibitor prevents elastase activation and surface cleavage of the epithelial sodium channel expressed in Xenopus laevis oocytes. 1709 May 46