PURPOSE: Pulmonary fibrosis is characterized by progressive worsening of pulmonary function leading to a high incidence of death. Currently, however, there has been little progress in the therapeutic strategies for pulmonary fibrosis. There have been several reports on cytokines being associated with lung fibrosis, including IL-6, TGF-β1. We recently reported two substances (ATRA and thalidomide) had preventive effects on pulmonary fibrosis by inhibiting IL-6-dependent proliferation and TGF-β1-dependent transdifferentiation of lung fibroblasts. Rheumatoid arthritis is a chronic autoimmune disorder, and its pathogenesis is also characterized by an association with several cytokines. It has been reported that Calpain, a calcium-dependent intracellular cysteine protease, plays an important role in the progression of Rheumatoid arthritis. In this study, we examined the preventive effect of Calpeptin, a calpain inhibitor, on bleomycin-induced pulmonary fibrosis.
METHODS: We performed histological examinations and quantitative measurements of IL-6, TGF-β1, collagen type Iα1, and angiopoietin-1 in bleomycin treated- mouse lung tissues with or without the administration of Calpeptin.
RESULTS: Calpeptin histologically ameliorated bleomycin-induced pulmonary fibrosis in mice. Calpeptin decreased the expression of IL-6, TGF-β1, angiopoietin-1, and collagen type Iα1 mRNA in mouse lung tissues. In vitro studies disclosed that Calpeptin reduced 1) production of IL-6, TGF-β1, angiopoietin-1 and collagen synthesis from lung fibroblasts, and 2) both IL-6-dependent proliferation and angiopoietin-1-dependent migration of the cells, which could be the mechanism underlying the preventive effect of Calpeptin on pulmonary fibrosis.
CONCLUSIONS: These data suggest the clinical use of Calpeptin for the prevention of pulmonary fibrosis.
CLINICAL IMPLICATIONS: This is the first report about the relationship between calpain and pulmonary fibrosis.
DISCLOSURE: The following authors have nothing to disclose: Chiharu Tabata, Rie Tabata, Takashi Nakano
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