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Dual Inhibition of Cathepsin G and Chymase Is Effective in Animal Models of Pulmonary Inflammation

¹ Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania; and ² Mount Sinai Medical Center, Miami Beach, Florida

Correspondence and requests for reprints should be addressed to Bruce E. Maryanoff, Ph.D., Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Roads, Spring House, PA 19477-0076. E-mail: bmaryano{at}scripps.edu

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) and chymase. From this 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 Cat G and 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, antigen-induced 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 OVA-sensitized 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.

Key Words: asthma • mast cells • neutrophils • pulmonary disease • serine protease • tobacco smoke • enzyme inhibitor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Mast cells and neutrophils play an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease, partly by releasing serine proteases, such as cathepsin G and chymase. It is not known if a dual inhibitor of neutrophil cathepsin G and mast cell chymase could ameliorate chronic pulmonary inflammation in vivo. What This Study Adds to the Field We examined the antiinflammatory pharmacology of RWJ-355871, a potent, dual inhibitor of cathepsin G and chymase, in three animal models of inflammation and determined that it exhibits notable efficacy. The results suggest potential therapeutic utility for treating airway inflammatory diseases that depend on cathepsin G and/or chymase.

 

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