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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Suplatast Tosilate Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice

Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan (M.F., N.H., T.T., T.S., N.I., K.F., Y.H., N.K.); and Department of Hematology and Respiratory Medicine, Kochi University, Kochi, Japan (A.Y.)

Increasing evidence suggests that the development of pulmonary fibrosis is a T helper (Th) 2-mediated process. Suplatast tosilate is a Th2 cytokine inhibitor that is widely used as an asthma controller in Japan. Therefore, we hypothesized that suplatast tosilate might have an inhibitory effect on the development of pulmonary fibrosis. To investigate this effect, suplatast tosilate was administered to mice after the intratracheal instillation of bleomycin (BLM). The effect of suplatast tosilate was studied by analysis of bronchoalveolar lavage (BAL) fluid and a hydroxyproline assay. We found that the treatment of mice with suplatast tosilate significantly reduced the degree of pulmonary fibrosis. Because a significantly elevated Th2 response was not detected in the C57BL/6 mice after BLM administration, the effect of suplatast tosilate on Th2 cytokines could not be demonstrated. Interestingly, however, the up-regulation of the monocyte chemoattractant protein (MCP)-1 levels in the BAL fluid was found to be suppressed. Following these results, we also demonstrated that suplatast tosilate effectively inhibited the production of MCP-1 in alveolar macrophages (AMs). These findings suggest that suplatast tosilate has both anti-inflammatory and antifibrotic effects, which were associated with a suppressed MCP-1 expression in AMs. Thus, suplatast tosilate, which is already widely used in Japan, may warrant further consideration as a potentially useful treatment for pulmonary fibrosis.

Address correspondence to: Noboru Hattori, Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail: nhattori{at}hiroshima-u.ac.jp