novel development research on the prevention and treatment of pulmonary fibrosis

近年来，我们报道了两种物质（全反式维甲酸和沙利度胺）通过抑制肺成纤维细胞IL-6依赖性增殖和TGF-β_1依赖性转分化而对肺纤维化有预防作用。类风湿性关节炎是一种慢性自身免疫性疾病，其发病机制也与多种细胞因子有关。钙蛋白酶（Calpain）是一种细胞内钙离子依赖性半胱氨酸蛋白酶，在风湿性关节炎的发生、发展中起重要作用。在这项研究中，我们研究了钙蛋白酶抑制剂Calpeptin对博莱霉素诱导的肺纤维化的预防作用。Calpeptin可降低小鼠肺组织中IL-6、TGF-β_1、Angiopoietin-1和I型胶原α1 mRNA的表达。体外研究发现，Calpeptin可抑制肺成纤维细胞产生IL-6、TGF-β_1、Angiopoietin-1和胶原合成，抑制肺成纤维细胞的IL-6依赖性增殖和Angiopoietin-1依赖性迁移，这可能是Calpeptin预防肺纤维化的机制之一，提示Calpeptin可用于预防肺纤维化的临床应用。

We recently reported two substances (ATRA and thalidomide) had preventive effects on pulmonary fibrosis by inhibiting IL-6-dependent proliferation and TGF-β_1-dependent transdifferentiation of lung fibroblasts. Rheumatoid arthritis is a chronic autoimmune disorder, and its pathogenesis is also characterized by an association with several cytokines. It has been reported that Calpain, a calcium-dependent intracellular cysteine protease, plays an important role in the progression of Rheumatoid arthritis. In this study, we examined the preventive effect of Calpeptin, a calpain inhibitor, on bleomycin-induced pulmonary fibrosis.Calpeptin histologically ameliorated bleomycin-induced pulmonary fibrosis in mice. Calpeptin decreased the expression of IL-6, TGF-β_1, angiopoietin-1, and collagen type Iα1 mRNA in mouse lung tissues. In vitro studies disclosed that Calpeptin reduced 1) production of IL-6, TGF-β_1, angiopoietin-1 and collagen synthesis from lung fibroblasts, and 2) both IL-6-dependent proliferation and angiopoietin-1-dependent migration of the cells, which could be the mechanism underlying the preventive effect of Calpeptin on pulmonary fibrosis.These data suggest the clinical use of Calpeptin for the prevention of pulmonary fibrosis.