Shi-Wen Xu, Rodríguez-Pascual Fernando, Lamas Santiago, Holmes Alan, Howat Sarah, Pearson Jeremy D, Dashwood Michael R, du Bois Roland M, Denton Christopher P, Black Carol M, Abraham David J, Leask Andrew
Centre for Rheumatology, Department of Medicine, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom.
Mol Cell Biol. 2006 Jul;26(14):5518-27. doi: 10.1128/MCB.00625-06.
The signal transduction mechanisms generating pathological fibrosis are almost wholly unknown. Endothelin-1 (ET-1), which is up-regulated during tissue repair and fibrosis, induces lung fibroblasts to produce and contract extracellular matrix. Lung fibroblasts isolated from scleroderma patients with chronic pulmonary fibrosis produce elevated levels of ET-1, which contribute to the persistent fibrotic phenotype of these cells. Transforming growth factor beta (TGF-beta) induces fibroblasts to produce and contract matrix. In this report, we show that TGF-beta induces ET-1 in normal and fibrotic lung fibroblasts in a Smad-independent ALK5/c-Jun N-terminal kinase (JNK)/Ap-1-dependent fashion. ET-1 induces JNK through TAK1. Fibrotic lung fibroblasts display constitutive JNK activation, which was reduced by the dual ETA/ETB receptor inhibitor, bosentan, providing evidence of an autocrine endothelin loop. Thus, ET-1 and TGF-beta are likely to cooperate in the pathogenesis of pulmonary fibrosis. As elevated JNK activation in fibrotic lung fibroblasts contributes to the persistence of the myofibroblast phenotype in pulmonary fibrosis by promoting an autocrine ET-1 loop, targeting the ETA and ETB receptors or constitutive JNK activation by fibrotic lung fibroblasts is likely to be of benefit in combating chronic pulmonary fibrosis.
引发病理性纤维化的信号转导机制几乎完全未知。内皮素-1（ET-1）在组织修复和纤维化过程中上调，可诱导肺成纤维细胞产生并收缩细胞外基质。从患有慢性肺纤维化的硬皮病患者中分离出的肺成纤维细胞产生的ET-1水平升高，这促成了这些细胞持续的纤维化表型。转化生长因子β（TGF-β）诱导成纤维细胞产生并收缩基质。在本报告中，我们表明TGF-β以一种不依赖Smad的、依赖ALK5/c-Jun氨基末端激酶（JNK）/Ap-1的方式在正常和纤维化的肺成纤维细胞中诱导ET-1。ET-1通过TAK1诱导JNK。纤维化的肺成纤维细胞表现出组成性JNK激活，双重ETA/ETB受体抑制剂波生坦可降低这种激活，这为自分泌内皮素环提供了证据。因此，ET-1和TGF-β可能在肺纤维化发病机制中协同作用。由于纤维化肺成纤维细胞中升高的JNK激活通过促进自分泌ET-1环而有助于肺纤维化中肌成纤维细胞表型的持续存在，靶向ETA和ETB受体或纤维化肺成纤维细胞的组成性JNK激活可能对对抗慢性肺纤维化有益。
