GM-CSF regulates bleomycin-induced pulmonary fibrosis via a prostaglandin-dependent mechanism
GM-CSF regulates bleomycin-induced pulmonary fibrosis via a prostaglandin-dependent mechanism
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DOI：
10.4049/jimmunol.165.7.4032
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发表时间：
2000-10-01
影响因子：
4.4
通讯作者：
Toews, GB
中科院分区：
文献类型：
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作者：
Moore, BB;Coffey, MJ;Toews, GB
为了表征GM-CSF在肺纤维化中的作用，我们在野生型小鼠和靶向缺失GM-CSF基因的小鼠（GM-CSF-/-小鼠）中研究了博莱霉素诱导的纤维化。没有GM-CSF，肺纤维化在组织学和定量上都更严重。这些变化与炎症细胞的增加募集无关，因为野生型和GM-CSF-/-小鼠在博莱霉素后向肺募集了相同数量的细胞。有趣的是，在GM-CSF-/-小鼠中没有嗜酸性粒细胞的募集。我们研究了GM-CSF-/-动物的纤维化反应增强是否由于内源性纤维发生下调因子的缺乏。生理盐水或博莱霉素处理小鼠的全肺匀浆分析显示，GM-CSF-/-动物的PGE水平降低(2)。此外，从暴露于博来霉素的野生型和GM-CSF-/-小鼠中采集肺泡巨噬细胞。尽管博来霉素治疗削弱了野生型小鼠肺泡巨噬细胞合成PGE的能力(2)，但GM-CSF-/-小鼠肺泡巨噬细胞合成PGE(2)的缺陷明显大于野生型细胞。向肺泡巨噬细胞外源性添加GM-CSF可逆转体外PGE(2)合成缺陷。在纤维形成阶段给野生型小鼠使用PG合成抑制剂吲哚美辛会加重纤维化的严重程度，这意味着PGE(2)缺乏在纤维化病变的演变中起着因果作用。这些数据表明，GM-CSF缺乏导致博莱霉素诱导的肺纤维化中纤维生成增强，并表明这种作用的一种机制是削弱了强效抗纤维化类二十烷酸PGE的产生(2)。
To characterize the role of GM-CSF in pulmonary fibrosis, we have studied bleomycin-induced fibrosis in wild-type mice vs mice with a targeted deletion of the GM-CSF gene (GM-CSF-/- mice). Without GM-CSF, pulmonary fibrosis was worse both histologically and quantitatively, These changes were not related to enhanced recruitment of inflammatory cells because wild-type and GM-CSF-/- mice recruited equivalent numbers of cells to the lung following bleomycin. Interestingly, recruitment of eosinophils was absent in GM-CSF-/- mice. We investigated whether the enhanced fibrotic response in GM-CSF-/- animals was due to a deficiency in an endogenous down-regulator of fibrogenesis. Analysis of whole lung homogenates from saline- or bleomycin-treated mice revealed that GM-CSF-/- animals had reduced levels of PGE(2). Additionally, alveolar macrophages were harvested from wild-type and GM-CSF-/- mice that had been exposed to bleomycin. Although bleomycin treatment impaired the ability of alveolar macrophages from wild-type mice to synthesize PGE(2), alveolar macrophages from GM-CSF-/- mice exhibited a significantly greater defect in PGE(2) synthesis than did wild-type cells. Exogenous addition of GM-CSF to alveolar macrophages reversed the PGE(2) synthesis defect in vitro. Administration of the PG synthesis inhibitor, indomethacin, to wild-type mice during the fibrogenic phase postbleomycin worsened the severity of fibrosis, implying a causal role for PGE(2) deficiency in the evolution of the fibrotic lesion. These data demonstrate that GM-CSF deficiency results in enhanced fibrogenesis in bleomycin-induced pulmonary fibrosis and indicate that one mechanism for this effect is impaired production of the potent antifibrotic eicosanoid, PGE(2).