Potency of Truncated Secretory Leukoprotease Inhibitor Assessed in Acute Lung Injury Models in Hamsters

  1. Hiroaki Mitsuhashi,
  2. Satoshi Asano,
  3. Takashi Nonaka,
  4. Ken-Ichi Masuda and
  5. Mamoru Kiyoki
  1. Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan

    Abstract

    We evaluated the potency of truncated secretory leukoprotease inhibitor (truncated SLPI) in a human sputum elastase (HSE)-induced lung injury model and in a specific neutrophil-mediated acute lung injury model in hamsters. Intratracheal administration of HSE induced acute lung hemorrhage that could be measured by determination of the hemoglobin content in the bronchoalveolar lavage fluid. Intratracheal administration of truncated SLPI 1 hr before HSE administration inhibited acute lung hemorrhage in a dose-dependent manner (ED50 = 46.8 μg/kg), as did i.v. injection of the inhibitor given 2 min before HSE administration (ED50 = 14.7 mg/kg). Intratracheal administration of endotoxin (lipopolysaccharide) induced pulmonary neutrophilia. Twenty-four hours after lipopolysaccharide administration, the addition of formyl-methionyl-leucyl-phenylalanine resulted in a neutrophil-dependent acute lung injury that expressed an increase in hemoglobin content and in elastase-like activity in bronchoalveolar lavage fluids. In this model, lung injury was significantly attenuated by i.v. and intratracheal administration of truncated SLPI. These results suggest that truncated SLPI appears to be a good candidate inhibitor for the treatment of destructive lung diseases due to neutrophils.

    Footnotes

    • Send reprint requests to: Hiroaki Mitsuhashi, Teijin Institute For Bio-Medical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191, Japan.

    • Abbreviations:
      truncated SLPI
      truncated secretory leukoprotease inhibitor
      HSE
      human sputum elastase
      BAL
      bronchoalveolar lavage
      LPS
      lipopolysaccharide
      FMLP
      formyl-methionyl-leucyl-phenylalanine
      CMK
      methoxysuccinyl-alanyl-alanyl-prolyl-valyl-chloromethyl-ketone
      SOD
      superoxide dismutase
      DFP
      diisopropyl fluorophosphate
      EDTA
      disodium ethylenediaminetetraacetate
      α1-PI
      α1-protease inhibitor
      PBS
      phosphate-buffered saline
      • Received October 7, 1996.
      • Accepted April 8, 1997.
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    1. JPET August 1, 1997 vol. 282 no. 2 1005-1010
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