Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice
Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice
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DOI：
10.4049/jimmunol.179.1.708
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发表时间：
2007-07-01
影响因子：
4.4
通讯作者：
Kubo, Hajime
中科院分区：
文献类型：
--
作者：
Tabata, Chiharu;Tabata, Rie;Kubo, Hajime
人类的肺纤维化可能是由于大量的条件而发生的。在特发性肺纤维化（IPF）中，肺功能逐渐受损，导致高死亡率。目前还没有有效的治疗IPF的方法。我们最近报道IL-6和TGF-β 1在肺成纤维细胞的增殖和分化中起重要作用，全反式维甲酸（ATRA）通过抑制这些细胞因子来预防博莱霉素诱导的肺纤维化。沙利度胺（塔尔）通过抑制IL-6依赖的细胞生长和血管生成而用于治疗多发性骨髓瘤。在这项研究中，我们检查了塔尔对博莱霉素诱导的小鼠肺纤维化的预防作用。我们对博莱霉素处理的小鼠肺组织进行了组织学检查和IL-6、TGF-β 1、I型胶原α I（COL 1A 1）、血管内皮生长因子（VEGF）、血管生成素-1（Ang-1）和血管生成素-2（Ang-2）的定量测量，并给予或不给予塔尔。泰国组织学改善博莱霉素诱导的小鼠肺组织纤维化。Thai可降低小鼠肺组织中IL-6、TGF-β 1、VEGF、Ang-1、Ang-2和COL 1A 1 mRNA的表达。此外，塔尔抑制肺中的血管生成。体外研究表明，塔尔可降低1）人肺成纤维细胞的IL-6、TGF-β（1）、VEGF、Ang-1和胶原合成，以及2）细胞的IL-6依赖性增殖和TGF-β（1）依赖性转分化，这可能是塔尔对肺纤维化预防作用的潜在机制。这些数据可能为探索塔尔预防肺纤维化的临床应用提供了依据。
Pulmonary fibrosis in humans can occur as a result of a large,number of conditions. In idiopathic pulmonary fibrosis (IPF), pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for IPF. We have recently reported that IL-6 and TGF-beta(1) plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid (ATRA) prevented bleomycin-induced lung fibrosis through, the inhibition of these cytokines. Thalidomide (Thal) has been used in the treatment of multiple myeloma through the inhibitory effect on IL-6-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced pulmonary fibrosis in mice. We performed histological examinations and quantitative measurements of IL-6, TGF-beta(1), collagen type I alpha I (COL1A1), vascular endothelial growth factor (VEGF), angiopoietih-1 (Ang-1) and anigiopoietin-2 (Ang-2) in bleomycin-treated mouse lung tissues with or Without the administration of Thal. Thai histologically ameliorated bleomycin-induced fibrosis in mouse lung tissues. Thai decreased the expressions of IL-6, TGF-beta(1), VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1) production of IL-6, TGF-beta(1), VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2) both IL-6-dependent proliferation and TGF-beta(1)-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on pulmonary fibrosis. These data may provide a rationale to explore clinical use of Thal for the prevention of pulmonary fibrosis.