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

肺纤维化是一种终末期疾病，目前尚无有效的治疗方法。尽管其发病机制尚不清楚，但肺纤维化是由各种炎症引起的。NKT细胞通过其糖脂配体的刺激产生大量细胞因子，从而调节炎症。在本研究中，我们研究了选择性NKT细胞配体α-半乳糖基神经酰胺(α-GalCer)在博莱霉素诱导的肺纤维化发展中的作用。用α-GalCer治疗小鼠，通过减轻肺纤维化的发展，延长了小鼠在博莱霉素注射下的存活时间。α-GalCer的保护作用与增加肺组织中的干扰素-γ水平，降低肺组织中纤维化细胞因子如转化生长因子-β和结缔组织生长因子的水平有关。α-GalCer可降低巨噬细胞炎性蛋白-2水平，减轻博莱霉素所致的初始肺炎症。在缺乏NKT细胞或经抗干扰素-γ抗体治疗的小鼠中，α-GalCer的保护作用显著降低。这些结果提示，α-GalCer可抑制博莱霉素诱导的急性肺炎症，从而减轻肺纤维化的发展，其机制可能与调节多种细胞因子水平有关。

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.