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Effect of ONO-5046, a specific neutrophil elastase inhibitor, on the phorbol myristate acetate-induced injury in isolated dog lung.

Abstract
Phorbol myristate acetate (PMA) activates neutrophils and causes acute lung injury. We determined the effect of ONO-5046, a specific neutrophil elastase inhibitor, on the increase in microvascular permeability induced by PMA in isolated dog lung perfused with autologous blood at a constant perfusion flow. The vascular permeability was assessed by the capillary filtration coefficient (Kf, c) and the solvent-drag reflection coefficient (sigma f). PMA (13.3 micrograms) increased vascular permeability, as evidenced by an increase in Kf, c from 0.18 +/- 0.02 to 0.92 +/- 0.14 mL/min/cmH2O/100 g and a decrease in sigma f to 0.35 +/- 0.01 as compared to control values of 0.69 +/- 0.06. The PMA-induced changes in Kf, c and sigma f were dose-dependently attenuated by pretreatment with ONO-5046 (2-20 mg). We conclude that ONO-5046 can effectively attenuate the PMA-induced injury in the isolated blood-perfused dog lungs.
AuthorsH G Wang, T Shibamoto, T Miyahara, H Haniu, S Tanaka, K Fujimoto, T Honda, K Kubo, S Koyama
JournalExperimental lung research (Exp Lung Res) 1999 Jan-Feb Vol. 25 Issue 1 Pg. 55-67 ISSN: 0190-2148 [Print] England
PMID10027079 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Serine Proteinase Inhibitors
  • Sulfonamides
  • Vasodilator Agents
  • Papaverine
  • sivelestat
  • Leukocyte Elastase
  • Tetradecanoylphorbol Acetate
  • Glycine
Topics
  • Animals
  • Capillary Permeability (drug effects)
  • Dogs
  • Female
  • Glycine (analogs & derivatives, pharmacology)
  • In Vitro Techniques
  • Leukocyte Elastase (antagonists & inhibitors)
  • Lung (blood supply, drug effects, enzymology)
  • Lung Diseases (chemically induced, enzymology)
  • Male
  • Papaverine (pharmacology)
  • Perfusion
  • Serine Proteinase Inhibitors (pharmacology)
  • Substrate Specificity
  • Sulfonamides (pharmacology)
  • Tetradecanoylphorbol Acetate (toxicity)
  • Vasodilator Agents (pharmacology)

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