The calpain inhibitor calpeptin prevents bleomycin-induced pulmonary fibrosis in mice
The calpain inhibitor calpeptin prevents bleomycin-induced pulmonary fibrosis in mice
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DOI：
10.1111/j.1365-2249.2010.04257.x
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发表时间：
2010-12-01
影响因子：
4.6
通讯作者：
Nakano, T.
中科院分区：
文献类型：
--
作者：
Tabata, C.;Tabata, R.;Nakano, T.
肺纤维化的特征是肺功能进行性恶化，导致死亡率高。然而，目前，肺纤维化的治疗策略进展甚微。已经有几份关于与肺纤维化相关的细胞因子的报告，包括白细胞介素（IL）-6和TGF-β 1。我们最近报道了两种物质（ATRA和沙利度胺）通过抑制肺成纤维细胞的IL-6依赖性增殖和TGF-β 1依赖性转分化而对肺纤维化具有预防作用。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。钙蛋白酶是一种细胞内钙离子依赖的半胱氨酸蛋白酶，在类风湿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。我们进行了组织学检查和定量测量IL-6，TGF-β 1，胶原I型α 1和血管生成素-1在博莱霉素治疗的小鼠肺组织与或不与钙蛋白酶肽的管理。钙蛋白酶肽在组织学上改善博莱霉素诱导的小鼠肺纤维化。Calpeptin降低小鼠肺组织中IL-6、TGF-β 1、Angiopoietin-1和I型胶原α 1 mRNA的表达。体外研究表明，钙蛋白酶肽降低（i）肺成纤维细胞的IL-6、TGF-β 1、血管生成素-1和胶原合成;和（ii）细胞的IL-6依赖性增殖和血管生成素-1依赖性迁移，这可能是钙蛋白酶肽对肺纤维化预防作用的潜在机制。这些数据表明钙肽酶素用于预防肺纤维化的临床用途。
P>Pulmonary fibrosis is characterized by progressive worsening of pulmonary function leading to a high incidence of death. Currently, however, there has been little progress in therapeutic strategies for pulmonary fibrosis. There have been several reports on cytokines being associated with lung fibrosis, including interleukin (IL)-6 and transforming growth factor (TGF)-beta 1. We reported recently that two substances (ATRA and thalidomide) have preventive effects on pulmonary fibrosis by inhibiting IL-6-dependent proliferation and TGF-beta 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. We performed histological examinations and quantitative measurements of IL-6, TGF-beta 1, collagen type I alpha 1 and angiopoietin-1 in bleomycin-treated mouse lung tissues with or without the administration of Calpeptin. Calpeptin histologically ameliorated bleomycin-induced pulmonary fibrosis in mice. Calpeptin decreased the expression of IL-6, TGF-beta 1, angiopoietin-1 and collagen type I alpha 1 mRNA in mouse lung tissues. In vitro studies disclosed that Calpeptin reduced (i) production of IL-6, TGF-beta 1, angiopoietin-1 and collagen synthesis from lung fibroblasts; and (ii) 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.