Increased bleomycin-induced lung injury in mice deficient in the transcription factor T-bet.
Increased bleomycin-induced lung injury in mice deficient in the transcription factor T-bet.
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DOI：
10.1152/ajplung.00006.2006
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发表时间：
2006-10
期刊：
影响因子：
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通讯作者：
Jianguo Xu;A. Mora;J. LaVoy;K. Brigham;M. Rojas
中科院分区：
文献类型：
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作者：
Jianguo Xu;A. Mora;J. LaVoy;K. Brigham;M. Rojas
物种间和物种内对博来霉素 (BLM) 引起的肺损伤和纤维化的敏感性不同的原因尚不清楚。由于 CD4+ T 淋巴细胞的 T 辅助细胞 (Th) 1 和 2（Th1 和 Th2）极化是影响 BLM 反应的因素之一，因此我们假设阻止 Th1 转录因子 T-bet 的表达将使 BLM 抗性 BALB/c 小鼠对 BLM 敏感。野生型和 T-bet 缺陷 (T-bet-/-) BALB/c 小鼠用 BLM 或盐水溶液气管内治疗。 BLM 治疗后，T-bet-/- 小鼠肺部的胶原蛋白含量在第 14 天增加了一倍，但野生型 BALB/c 小鼠的肺部不受影响。这些发现通过组织病理学切片的胶原染色得到证实。 BLM 治疗在第 14 天时显着增加了 T-bet-/- 小鼠的呼吸频率并减少了潮气量，但对野生型小鼠没有影响。 BLM 治疗的 T-bet-/- 小鼠的肺纤维化与 Th2 细胞因子循环水平增加和促纤维化因子转化生长因子-β1 表达增加有关。 T-bet-/- 小鼠中 CD4+（而非 CD8+）T 细胞的耗竭减少了 BLM 诱导的肺纤维化和转化生长因子-β1 的表达。这些数据表明 CD4+ T 淋巴细胞中的 T-bet 途径可以赋予 BALB/c 小鼠对 BLM 诱导的肺纤维化的抵抗力。
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.