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

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.

• Authors: Bruce E Maryanoff, Lawrence de Garavilla, Michael N Greco, Barbara J Haertlein, Grace I Wells, Patricia Andrade-Gordon, William M Abraham
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 181 Issue 3 Pg. 247-53 (Feb 01 2010) ISSN: 1535-4970 [Electronic] United States
• PMID: 19875688 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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