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

Am J Respir Crit Care Med. 2010 Feb 1;181(3):247-53. doi: 10.1164/rccm.200904-0627OC. Epub 2009 Oct 29.

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) 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cathepsin G / antagonists & inhibitors*
  • Cathepsin G / metabolism
  • Chymases / antagonists & inhibitors*
  • Chymases / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Injections, Intravenous
  • Lung Diseases / drug therapy
  • Lung Diseases / enzymology*
  • Mice
  • Organophosphonates / administration & dosage
  • Organophosphonates / therapeutic use*
  • Piperidines / administration & dosage
  • Piperidines / therapeutic use*
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Pulmonary Disease, Chronic Obstructive / enzymology*
  • Rats
  • Sheep
  • Treatment Outcome

Substances

  • Biomarkers
  • JNJ-10311795
  • Organophosphonates
  • Piperidines
  • Cathepsin G
  • Chymases