Constitutive ALK5-independent c-Jun N-terminal kinase activation contributes to endothelin-1 overexpression in pulmonary fibrosis: evidence of an autocrine endothelin loop operating through the endothelin A and B receptors.
Constitutive ALK5-independent c-Jun N-terminal kinase activation contributes to endothelin-1 overexpression in pulmonary fibrosis: evidence of an autocrine endothelin loop operating through the endothelin A and B receptors.
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DOI：
10.1128/mcb.00625-06
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发表时间：
2006-07-01
影响因子：
5.3
通讯作者：
Leask, Andrew
中科院分区：
文献类型：
--
作者：
Shi-Wen, Xu;Rodriguez-Pascual, Fernando;Leask, Andrew
引起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表达上调，诱导肺成纤维细胞产生和收缩细胞外基质。从慢性肺纤维化硬皮病患者分离的肺成纤维细胞产生高水平的ET-1，这有助于这些细胞的持续纤维化表型。转化生长因子（tgf - β）诱导成纤维细胞产生和收缩基质。在本报告中，我们发现tgf - β在正常和纤维化肺成纤维细胞中以smad独立的ALK5/c-Jun n -末端激酶(JNK)/ ap -1依赖的方式诱导ET-1。ET-1通过TAK1诱导JNK。纤维化肺成纤维细胞显示组成性JNK激活，这种激活被双ETA/ETB受体抑制剂波生坦降低，提供了自分泌内皮素环的证据。因此，ET-1和tgf - β可能在肺纤维化的发病机制中协同作用。由于纤维化性肺成纤维细胞中JNK激活的升高通过促进自分泌ET-1环有助于肺纤维化中肌成纤维细胞表型的持久性，因此靶向ETA和ETB受体或纤维化性肺成纤维细胞的组成性JNK激活可能有益于对抗慢性肺纤维化。
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.