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The effects of α-galactosylceramide on the development of bleomycin-induced pulmonary fibrosis

α-半乳糖神经酰胺对博莱霉素诱导的肺纤维化发展的影响

基本信息

批准号：
14570537
负责人：
ISHII Yukio
金额：
$ 1.86万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Pulmonary fibrosis is an end-stage disorder for which efficacious therapeutic options are not readily available. Although its pathogenesis is poorly understood, pulmonary fibrosis occurs as a result of various inflammations. NKT cells modulate inflammation because of their ability to produce large amounts of cytokines by stimulation with their glycolipid ligand. In the present study, we investigated the effects of alpha-galactosylceramide (alpha-GalCer), a selective NKT cell ligand, on the development of bleomycin-induced pulmonary fibrosis. Treatment of mice with alpha-GalCer prolonged their survival under bleomycin administration by attenuating the development of pulmonary fibrosis. The protective effects of alpha-GalCer were associated with an increase in the pulmonary level of IFN-gamma and a decrease in the pulmonary level of fibrogenic cytokines such as TGF-beta and connective tissue growth factor. The initial pulmonary inflammation caused by bleomycin was also attenuated by alpha-GalCer with the reduction of the macrophage inflammatory protein-2 level. The protective effects of alpha-GalCer were markedly reduced in mice lacking NKT cells or as a result of treatment with anti-IFN-gamma antibody. These results suggest that alpha-GalCer suppresses bleomycin-induced acute pulmonary inflammation and thus attenuates the development of pulmonary fibrosis possibly by regulating several cytokine levels.

肺纤维化是一种终末期疾病，其有效的治疗选择并不容易获得。虽然其发病机制知之甚少，但肺纤维化是各种炎症的结果。NKT细胞调节炎症，因为它们能够通过其糖脂配体的刺激产生大量细胞因子。在本研究中，我们研究了α-半乳糖神经酰胺（α-GalCer），一种选择性NKT细胞配体，对博来霉素诱导的肺纤维化的发展的影响。用α-GalCer治疗小鼠通过减弱肺纤维化的发展延长了它们在博来霉素施用下的存活。α-GalCer的保护作用与IFN-γ的肺水平的增加和诸如TGF-β和结缔组织生长因子的纤维化细胞因子的肺水平的降低相关。博莱霉素引起的初始肺部炎症也被α-GalCer减弱，巨噬细胞炎性蛋白-2水平降低。α-GalCer的保护作用在缺乏NKT细胞的小鼠中或作为用抗IFN-γ抗体治疗的结果而显著降低。这些结果表明，α-GalCer抑制博莱霉素诱导的急性肺部炎症，从而可能通过调节几种细胞因子水平来减弱肺纤维化的发展。