Dual inhibition of cathepsin G and chymase is effective in animal models of pulmonary inflammation

Bruce E. Maryanoff, Lawrence De Garavilla, Michael N. Greco, Barbara J. Haertlein, Grace I. Wells, Patricia Andrade-Gordon, William M. Abraham

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Rationale: Mast cells and neutrophils are key contributors to the pathophysiological inflammatory processes that underpin asthma and chronic obstructive pulmonary disease, partly through the release of noxious serine proteases, including cathepsin G (Cat G) andchymase.Fromthis standpoint, a dual inhibitor of neutrophil Cat G and mast cell chymase could protect against these disease-related inflammatory responses. Objectives: We examined the antiinflammatory pharmacology of RWJ-355871, a dual inhibitor of CatGand chymase, in animal models of inflammation that evince pathophysiological pathways relevant to asthma and chronic obstructive pulmonary disease to determine the therapeutic potential of this compound. Methods: In an ovalbumin (OVA)-sensitized rat model, RWJ-355871 was administered to block the mast-cell-mediated increase in paw volume caused by OVA injection. In a sheep asthma model, antigeninduced airway responses were assessed with and without aerosol treatment with RWJ-355871. In a murine tobacco-smoke model of airway inflammation, the effect of RWJ-355871 on smoke-induced neutrophilia was determined. Measurements and Main Results: Intravenous treatment of OVAsensitized rats with RWJ-355871 provided dose-dependent reduction in the increase in rat paw volume. In allergic sheep, aerosol pretreatment with RWJ-355871 showed dose-dependent inhibition of the antigen-induced early response, late response, and post-antigen-induced airway hyperreponsiveness. In tobacco-smoke-exposed mice, nebulized RWJ-355871 significantly reduced the smoke-induced neutrophilia from the levels observed in untreated mice. Conclusions: The preclinical antiinflammatory effects of RWJ-355871 in these animal models of inflammation indicate that this dual inhibitor may have therapeutic utility for treating airway inflammatory diseases involving mechanisms that depend on Cat G and/or chymase.

Original languageEnglish (US)
Pages (from-to)247-253
Number of pages7
JournalAmerican journal of respiratory and critical care medicine
Volume181
Issue number3
DOIs
StatePublished - Feb 1 2010

Keywords

  • Asthma
  • Enzyme inhibitor
  • Mast cells
  • Neutrophils
  • Pulmonary disease
  • Serine protease
  • Tobacco smoke

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Maryanoff, B. E., De Garavilla, L., Greco, M. N., Haertlein, B. J., Wells, G. I., Andrade-Gordon, P., & Abraham, W. M. (2010). Dual inhibition of cathepsin G and chymase is effective in animal models of pulmonary inflammation. American journal of respiratory and critical care medicine, 181(3), 247-253. https://doi.org/10.1164/rccm.200904-0627OC