Attenuation of lung inflammation and fibrosis in interferon-γ-deficient mice after intratracheal bleomycin
Attenuation of lung inflammation and fibrosis in interferon-γ-deficient mice after intratracheal bleomycin
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DOI：
10.1165/ajrcmb.24.5.4064
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发表时间：
2001-05-01
影响因子：
6.4
通讯作者：
Moller, DR
中科院分区：
文献类型：
--
作者：
Chen, ES;Greenlee, BM;Moller, DR
由于对博来霉素敏感的小鼠品系，如C57 BL/6 J，倾向于产生T辅助细胞1型（Th 1）细胞因子以响应免疫激活，我们假设对博来霉素的炎症反应部分是由局部产生的Th 1细胞因子干扰素-γ（IFN-γ）介导的。与这一假设一致，与纤维化抗性BALB/c小鼠或生理盐水对照小鼠相比，纤维化易感C57 BL/6 J和A/J小鼠在24 h时支气管肺泡灌洗液中IFN-γ蛋白的表达显著升高（通过酶联免疫吸附测定），随后在气管内给予博来霉素后10 d，肺部炎症、体重减轻和死亡率增加。为了直接确定IFN-γ在博来霉素毒性中的作用，我们将IFN-γ基因纯合无效突变（IFN-γ [-/-]）的C57 BL/6 J小鼠和野生型C57 BL/6 J小鼠暴露于子宫内博来霉素。与对照小鼠相比，IFN-γ（-/-）小鼠在5 U/kg博莱霉素腹腔内给药后10天表现出显著较低的实质炎症、体重减轻和死亡率。在1.5 U/kg博莱霉素暴露后3周，与野生型C57 BL/6 J小鼠相比，IFN-γ（-/-）小鼠通过羟脯氨酸测定确定的单肺胶原蛋白显著降低。总之，这些结果表明IFN-γ部分介导博来霉素诱导的肺部炎症和纤维化。
Because mouse strains susceptible to bleomycin, such as C57BL/6J, tend to produce T helper type 1 (Th1) cytokines in response to immune activation, we hypothesized that the inflammatory response to bleomycin is mediated, in part, by local production of the Th1 cytokine interferon-gamma (IFN-gamma). Consistent with this hypothesis, fibrosis-prone C57BL/6J and A/J mice demonstrated significantly elevated expression of IFN-gamma protein (by enzyme-linked immunosorbent assay) in bronchoalveolar lavage fluid at 24 h, and subsequently increased lung inflammation, weight loss, and mortality 10 d after intratracheal bleomycin administration compared with fibrosis-resistant BALB/c mice or saline control mice. To directly determine a role for IFN-gamma in bleomycin toxicity, we exposed C57BL/6J mice with a homozygous null mutation of the IFN-gamma gene (IFN-gamma[-/-]) and wildtype C57BL/6J mice to intratracheal bleomycin. IFN-gamma(-/-) mice demonstrated significantly lower parenchymal inflammation, weight loss, and mortality 10 d after 5 U/kg intratracheal bleomycin administration compared with control mice. At 3 wk after 1.5 U/kg bleomycin exposure, single lung collagen determined by hydroxyproline assay was significantly lower in IFN-gamma(-/-) mice compared with wild-type C57BL/6J mice. Together, these results suggest that IFN-gamma mediates, in part, bleomycin-induced pulmonary inflammation and fibrosis.