Published ahead of print on March 30, 2007, doi:10.1164/rccm.200701-054OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200701-054OC
Chronic Asthma–induced Airway Remodeling Is Prevented by Toll-like Receptor-7/8 Ligand S284631 Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada; 2 Department of Pulmonary Medicine, Tokyo Medical and Dental University, Tokyo, Japan; 3 Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada; 4 Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; 5 Research Institute of the McGill University Health Center, Montreal, Quebec, Canada; 6 Department of Pathology, Montreal Neurological Hospital, McGill University, Montreal, Quebec, Canada; and 7 Department of Human Genetics, McGill University, Montreal, Quebec, Canada Correspondence and requests for reprints should be addressed to Danuta Radzioch, Ph.D., Department of Experimental Medicine, McGill University, Montreal, PQ, H3G 1A4 Canada. E-mail: danuta.radzioch{at}muhc.mcgill.ca Rationale: Allergic asthma is a heterogeneous disease, the pathology of which is a result of improper immune responses to innocuous antigens. We and others have previously shown that one of the Toll-like receptor (TLR)-7/8 ligands, the synthetic compound S28463 (resiquimod, R-848), is able to inhibit acute allergic asthma in mice. Objectives: Given that the efficiency of this pharmacologic compound against the smooth muscle mass increase and goblet cell hyperplasia that are characteristic of chronic allergic asthma has not been previously assessed, we investigated the ability of this compound to prevent these aspects of chronic airway remodeling. Methods: The impact of S28463 treatment was assessed in a Brown Norway rat model of chronic asthma by histologic, morphometric, and molecular techniques. Measurements and Main Results: We demonstrate that treatment with S28463 is able to prevent the development of goblet cell hyperplasia and increases in airway smooth muscle mass, and that this effect is at least partially mediated by inhibiting proliferation of goblet and smooth muscle cells, respectively. Furthermore, we show that the abrogation of airway remodeling is preceded by inhibition of the inflammatory reaction normally occurring in response to allergen challenge in sensitized animals. This inhibition was associated with a reduction of both helper T cell type 1 and type 2 cytokine protein expression in the lungs, demonstrating the potent antiinflammatory effect of this pharmaceutical compound in the context of allergic reactions. Conclusions: Taken together, our results indicate great potential for the use of S28463 as an antiinflammatory therapeutic agent for the management of chronic asthma.
Key Words: resiquimod • R-848 • imidazoquinoline • airway remodeling • Toll-like receptor
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