Increased bleomycin-induced lung injury in mice deficient in the transcription factor T-bet.
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-beta1. Depletion of CD4+, but not CD8+, T cells in T-bet-/- mice diminished BLM-induced lung fibrosis and the expression of transforming growth factor-beta1. These data suggest that the T-bet pathway in CD4+ T lymphocytes can confer resistance to BLM-induced lung fibrosis in BALB/c mice.
Xu
Jianguo
J
Division of Pulmonary, Allergy, and Critical Care Medicine, Center for Translational Research of the Lung, Emory University School of Medicine, Atlanta, GA 30322, USA.
Mora
Ana L
AL
LaVoy
John
J
Brigham
Kenneth L
KL
Rojas
Mauricio
M
D000818:Animals; D001761:Bleomycin; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004198:Disease Susceptibility; D006133:Growth Substances / Q000097:blood; D047589:Leukocyte Reduction Procedures; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D012720:Severity of Illness Index; D020825:T-Box Domain Proteins / Q000172:deficiency*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D000098815:T-bet Transcription Factor
D016207:Cytokines; D006133:Growth Substances; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin