Role of interferon-gamma in the evolution of murine bleomycin lung fibrosis.
Role of interferon-gamma in the evolution of murine bleomycin lung fibrosis.
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发表时间：
2003
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通讯作者：
M. Segel;G. Izbicki;Pazit Y. Cohen;R. Or;T. Christensen;S. B. Wallach-Dayan;R. Breuer
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作者：
M. Segel;G. Izbicki;Pazit Y. Cohen;R. Or;T. Christensen;S. B. Wallach-Dayan;R. Breuer
博莱霉素处理的C57BL/6小鼠肺细胞(LC)中干扰素-γ的产生上调。本研究描述了博莱霉素性肺损伤的时间进程、细胞来源和干扰素-γ表达的调节。博莱霉素组小鼠肺组织中干扰素-γ的mRNA在气管内滴注后3d达高峰。6d时，干扰素-γ蛋白表达水平升高，表达干扰素-γ的LC细胞百分率增加。CD4+、CD8+和自然杀伤细胞均对干扰素-γ的产生有显著贡献。博莱霉素处理组小鼠LC中IL-12mRNA水平在1d时升高。抗IL-12和抗IL-18抗体减少了这些细胞产生的干扰素-γ。为了确定内源性干扰素-γ在博莱霉素肺损伤的演变中的作用，我们比较了博莱霉素在小鼠、干扰素-γ基因的定向敲除突变(干扰素-伽马基因敲除)和野生型小鼠中的作用。在气管内注入博莱霉素后第14天，与野生型动物相比，干扰素-γ基因敲除者的总支气管肺泡灌洗液细胞计数和肺组织羟脯氨酸减少。肝纤维化的形态计量学参数无明显差异。我们的数据显示，博莱霉素治疗的小鼠肺内干扰素-γ的增加至少部分依赖于IL-12和IL-18。在干扰素-γ基因敲除的小鼠中缺乏干扰素-γ并不会增加肺纤维化。内源性干扰素-γ可能在博莱霉素性肺纤维化中起促炎症或促纤维化作用。
IFN-gamma production is upregulated in lung cells (LC) of bleomycin-treated C57BL/6 mice. The present study characterizes the time course, cellular source, and regulation of IFN-gamma expression in bleomycin-induced lung injury. IFN-gamma mRNA in LC from bleomycin-treated mice peaked 3 days after intratracheal instillation. IFN-gamma protein levels were increased at 6 days, as was the percentage of LC expressing IFN-gamma. CD4+, CD8+, and natural killer cells each contributed significantly to IFN-gamma production. IL-12 mRNA levels were increased at 1 day in LC of bleomycin-treated mice. Anti-IL-12 and anti-IL-18 antibodies decreased IFN-gamma production by these cells. To define the role of endogenous IFN-gamma in the evolution of bleomycin lung injury, we compared the effect of bleomycin in mice with a targeted knockout mutation of the IFN-gamma gene (IFN-gamma knockout) and wild-type mice. At 14 days after intratracheal bleomycin, total bronchoalveolar lavage cell counts and lung hydroxyproline were decreased in IFN-gamma knockouts compared with wild-type animals. There was no difference in morphometric parameters of fibrosis. Our data show that enhanced IFN-gamma production in the lungs of bleomycin-treated mice is at least partly IL-12 and IL-18 dependent. Absence of IFN-gamma in IFN-gamma knockout mice does not increase pulmonary fibrosis. Endogenous IFN-gamma may play a proinflammatory or profibrotic role in bleomycin-induced lung fibrosis.