Biphasic effects of free radical scavengers against bleomycin-induced pulmonary fibrosis

Abstract

Oxidative stress plays a critical role in the development of pulmonary fibrosis. However, the effects of treatment with anti-oxidant agents against pulmonary fibrosis have not yet been thoroughly investigated. In this study, the effect of MCI-186, a novel free radical scavenger, on bleomycin-induced pulmonary fibrosis was investigated. Bleomycin (0.05 units/mouse) was administered intratracheally into C57Bl/6 mice. MCI-186 was given to bleomycin-treated mice intraperitoneally from (i) day −3 to day 7, or from (ii) day 10 to day 28 after bleomycin administration in successive days. At 28 days after bleomycin administration, pulmonary fibrosis was then assessed by lung histology and hydroxyproline. MCI-186 inhibited H 2O 2-induced DNA damage in bronchial epithelium in vitro. MCI-186 decreased the lipid peroxide content, a marker for DNA damage, in the lung and reduced 8-OHdG positive cells in the lung in vivo. During the early period (day −3 to day 7) administration, MCI-186 partially attenuated bleomycin-induced pulmonary fibrosis. However, during the late period (day 10 to day 28) MCI-186 exacerbated pulmonary fibrosis, based on the histology and hydroxyproline content. In this condition, MCI-186 in the late period decreased the number of apoptosis cells induced by bleomycin, and therefore it might contribute to the deterioration of pulmonary fibrosis. These data indicate that MCI-186, radical scavenger, has a biphasic effect on bleomycin-induced pulmonary fibrosis in mice. Careful attention should be paid before clinical application of new remedies for pulmonary fibrosis.