Document Detail


Effects of a neutrophil elastase inhibitor (ONO-5046) on acute pulmonary injury induced by tumor necrosis factor alpha (TNFalpha) and activated neutrophils in isolated perfused rabbit lungs.
MedLine Citation:
PMID:  9445283     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The aim of this study was to examine the effect of ONO-5046, a neutrophil elastase (NE) inhibitor, on a model of acute lung injury induced by tumor necrosis factor alpha (TNFalpha) and phorbol myristate acetate (PMA)-activated neutrophils in isolated perfused rabbit lungs. 120 min after TNFalpha (4,000 JRU/ml) was injected into the pulmonary artery (PA), 5 x 10(7) PMA-stimulated neutrophils were infused into the PA together with 1251-rabbit serum albumin (RSA). In the ONO-5046-treated group (ONO), ONO-5046 (20 mg/kg/h) was continuously infused during the experimental period from 30 min prior to neutrophil administration. Saline, the ONO-5046 vehicle, was infused instead of ONO-5046 in the positive control group (ALD) and nonactivated neutrophils were infused without TNFalpha in the negative control group (Cont). PA pressure was monitored over a 240 min period, and bronchoalveolar lavage (BAL) was performed at the end of the experiment. Lung tissues were examined immunohistochemically for the expression of thrombomodulin (TM). The levels of TM in the perfusate were also measured by ELISA and the radioactivities in the BAL fluid, lung tissue and perfusate were determined to calculate the permeability index (PI) as an indicator of alveolar septal or vascular endothelial damage. The rabbit lungs infused with ONO-5046 showed slower and less increases in PA pressure compared with ALD group. The PI was significantly higher in ALD group (PI[BAL] = 0.028 +/- 0.014, PI[LUNG] = 0.04 +/- 0.003) than Cont (PI[BAL] = 0.002 +/- 0.001, PI[LUNG] = 0.015 +/- 0.003) and ONO group (PI[BAL] = 0.004 +/- 0.003, PI[LUNG] = 0.028 +/- 0.003 (p < 0.05). ALD group had higher TM levels in the perfusate and showed decreased expression of TM on the vascular endothelium compared to Cont and ONO group, suggesting that there was shedding of TM on endothelium and ONO-5046 attenuated a shedding of TM. In conclusion, ONO-5046 attenuated acute lung injury by inhibiting the alveolar epithelial and vascular endothelial injury triggered by activated neutrophils. NE appears to play an important role in the neutrophil-induced increase of pulmonary epithelial and microvascular permeability observed in acute lung injury.
Authors:
Y Miyazaki; T Inoue; M Kyi; M Sawada; S Miyake; Y Yoshizawa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  157     ISSN:  1073-449X     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  1998 Jan 
Date Detail:
Created Date:  1998-02-05     Completed Date:  1998-02-05     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  89-94     Citation Subset:  AIM; IM    
Affiliation:
First Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Capillary Permeability / drug effects
Carcinogens
Disease Models, Animal*
Drug Evaluation, Preclinical
Glycine / analogs & derivatives*,  therapeutic use
Infusions, Intravenous
Leukocyte Elastase / antagonists & inhibitors*
Neutrophil Activation*
Pulmonary Wedge Pressure / drug effects
Rabbits
Respiratory Distress Syndrome, Adult / chemically induced*,  drug therapy*,  immunology
Serine Proteinase Inhibitors / therapeutic use*
Sulfonamides / therapeutic use*
Tetradecanoylphorbol Acetate
Tumor Necrosis Factor-alpha / adverse effects*
Chemical
Reg. No./Substance:
0/Carcinogens; 0/Serine Proteinase Inhibitors; 0/Sulfonamides; 0/Tumor Necrosis Factor-alpha; 127373-66-4/ONO 5046; 16561-29-8/Tetradecanoylphorbol Acetate; 56-40-6/Glycine; EC 3.4.21.37/Leukocyte Elastase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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