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Am J Physiol Lung Cell Mol Physiol (April 28, 2006). doi:10.1152/ajplung.00006.2006
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Submitted on January 4, 2006
Accepted on April 17, 2006

Increased Bleomycin-Induced Lung Injury in Mice Deficient of the Transcription Factor T-bet

Jianguo Xu1, Ana L. Mora2, John LaVoy1, Kenneth L. Brigham2, and Mauricio Rojas2*

1 Division of Pulmonary, Allergy and Critical Care Medicine; Center for Translational Research in the Lung
2 Division of Pulmonary, Allergy and Critical Care Medicine; Center for Translational Research in the Lung; Medicine, McKelvey Center for Lung Transplantation, Atlanta, Georgia, United States

* To whom correspondence should be addressed. E-mail: mrojas{at}emory.edu.

{beta}The reasons for variable sensitivity among and within species to lung injury and fibrosis caused by bleomycin are unknown. Since Th1-Th2 polarization of CD4+ T lymphocytes is one of the factors that affects the bleomycin response, we hypothesized that preventing expression of the Th1 transcription factor, T-bet, would render bleomycin resistant BALB/c mice sensitive to bleomycin. Wild type and T-bet deficient (T-bet-/-) BALB/c mice were treated with bleomycin or saline solution intratracheally. After bleomycin, collagen content in the lung in T-bet-/- mice doubled by day 14; collagen content in lungs from wild type BALB/c mice was unaffected by bleomycin. Those findings were confirmed by collagen staining of histopathological sections. Consistently, in bleomycin treated T-bet-/- mice, respiratory frequency increased and tidal volume decreased significantly by day 14 while respiratory variables were unaffected by bleomycin in wild type mice. Lung fibrosis in T-bet-/- mice after bleomycin treatment was associated with increased circulating levels of Th2 cytokines and increased expression of the pro-fibrotic factor TGF-{beta}1. Depletion of CD4+ (but not CD8+) T cells in T-bet deficient mice diminished bleomycin-induced lung fibrosis, and expression of TGF-{beta}1. These data suggest that T-bet pathway in CD4+ T lymphocytes can be one of the elements that confers resistance to bleomycin induced lung fibrosis in BALB/c mice.




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