Increased bleomycin-induced lung injury in mice deficient in the transcription factor T-bet

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Abstract
The reasons for variable sensitivity among and within species to lung injury and fibrosis caused by bleomycin (BLM) are unknown. Because T helper (Th) 1 and 2 (Th1 and Th2) polarization of CD4+ T lymphocytes is one of the factors that affects the BLM response, we hypothesized that preventing expression of the Th1 transcription factor T-bet would render BLM-resistant BALB/c mice sensitive to BLM. Wild-type and T-bet-deficient (T-bet−/−) BALB/c mice were treated with BLM or saline solution intratracheally. After BLM treatment, collagen content in the lung increased twofold by day 14 in lungs from T-bet−/− mice but was unaffected in lungs from wild-type BALB/c mice. These findings were confirmed by collagen staining of histopathological sections. BLM treatment significantly increased respiratory frequency and decreased tidal volume by day 14 in T-bet−/− mice but had no effect in wild-type mice. Lung fibrosis in BLM-treated T-bet−/− mice was associated with increased circulating levels of Th2 cytokines and increased expression of the profibrotic factor transforming growth factor-β1. Depletion of CD4+, but not CD8+, T cells in T-bet−/− mice diminished BLM-induced lung fibrosis and the expression of transforming growth factor-β1. These data suggest that the T-bet pathway in CD4+ T lymphocytes can confer resistance to BLM-induced lung fibrosis in BALB/c mice.