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

American Journal of Respiratory and Critical Care Medicine
Y MiyazakiY Yoshizawa

Abstract

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...Continue Reading

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