Effects of a synthetic protease inhibitor (gabexate mesilate) and a neutrophil elastase inhibitor (sivelestat sodium) on acid-induced lung injury in rats

Eur J Pharmacol. 2010 Sep 1;641(2-3):220-5. doi: 10.1016/j.ejphar.2010.05.039. Epub 2010 Jun 11.

Abstract

The present study was designed to examine the combined effects of a synthetic protease inhibitor, gabexate mesilate, with a specific neutrophil elastase inhibitor, sivelestat sodium, on acid-induced lung injury. Adult male Sprague-Dawley rats weighing 300-350 g were anaesthetised intraperitoneally with pentobarbitone sodium and the right jugular vein was cannulated. Following tracheostomy, rats were ventilated mechanically and underwent intratracheal instillation of hydrochloric acid (HCl, 0.1N 1.5 ml/kg) or normal saline. Gabexate mesilate (10mg/kg, i.p.) and/or sivelestat sodium (10mg/kg/h, i.v.) were administered 30 min before HCl instillation. Bronchoalveolar lavage fluid samples were obtained 5h after HCl instillation. In bronchoalveolar lavage fluid, the HCl-induced increases in total nucleated cell counts, neutrophil counts, optical density at 412 nm as an index of pulmonary haemorrhage, concentrations of albumin and cytokine-induced neutrophil chemoattractant (CINC) were significantly attenuated by either gabexate mesilate or sivelestat sodium treatment. Gabexate mesilate or sivelestat sodium treatment also significantly attenuated the wet to dry weight ratio induced by HCl. However, combined treatment with both gabexate mesilate and sivelestat sodium did not show additive effects on HCl-induced lung injury, compared with single treatments. These findings suggested that gabexate mesilate and sivelestat sodium each exhibited protective effects on acid-induced lung injury, but that synergistic effects of both agents are limited in this acid-induced lung injury model.

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Drug Therapy, Combination
  • Gabexate / administration & dosage*
  • Gabexate / adverse effects
  • Glycine / administration & dosage
  • Glycine / analogs & derivatives*
  • Hydrochloric Acid
  • Leukocyte Count
  • Lung Injury / chemically induced
  • Lung Injury / drug therapy*
  • Male
  • Neutrophils / drug effects
  • Protease Inhibitors / administration & dosage*
  • Protease Inhibitors / adverse effects
  • Proteinase Inhibitory Proteins, Secretory / administration & dosage
  • Proteinase Inhibitory Proteins, Secretory / therapeutic use*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Sodium / adverse effects
  • Sodium / pharmacology
  • Sulfonamides / administration & dosage*

Substances

  • Protease Inhibitors
  • Proteinase Inhibitory Proteins, Secretory
  • Sulfonamides
  • Gabexate
  • Sodium
  • sivelestat
  • Hydrochloric Acid
  • Glycine