Discoidin domain receptor 1 contributes to the survival of lung fibroblast in idiopathic pulmonary fibrosis (Retracted Article)
Discoidin domain receptor 1 contributes to the survival of lung fibroblast in idiopathic pulmonary fibrosis (Retracted Article)
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DOI：
10.2353/ajpath.2006.050801
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发表时间：
2006-03-01
影响因子：
6
通讯作者：
Arimura, K
中科院分区：
文献类型：
--
作者：
Matsuyama, W;Watanabe, M;Arimura, K
特发性肺纤维化（IPF）的特征是成纤维细胞增殖和细胞外基质（包括胶原蛋白）的积累，是一种导致肺重塑和纤维化的慢性进行性疾病。然而，可能使成纤维细胞抵抗细胞凋亡的细胞机制尚未完全阐明。盘状结构域受体 I (DDR1) 是一种受体酪氨酸激酶，其配体是胶原蛋白，在体内表达，并在体外有助于白细胞分化和核因子 (NF)-κ B 激活，可能在成纤维细胞存活中发挥重要作用。在这项研究中，我们使用从 IPF 和非 IPF 患者获得的成纤维细胞检查了体内和体外 DDR1 表达及其在细胞存活中的作用。免疫组织化学显示，成纤维细胞灶中的成纤维细胞表达内源性 DDR1。 IPF 患者的成纤维细胞中 DDR1 表达水平显着升高，主要亚型是 DDR1b。在 IPF 患者中，成纤维细胞中 DDR1 的激活抑制了 Fas 配体诱导的细胞凋亡，并导致 NF-κ B 核转位。通过 siRNA 抑制成纤维细胞中 DDR1 的表达，消除了这些作用，而 NF-κ B 抑制剂则消除了 DDR1 激活的抗凋亡作用。我们认为 DDR1 有助于 IPF 组织微环境中成纤维细胞的存活，并且 DDR1 上调也可能发生在其他纤维增殖性肺部疾病中。
Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor I (DDR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-kappa B activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro DDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DDR1. The DDR1 expression level was significantly higher in fibroblasts from IPF patients, and the predominant isoform was DDR1b. In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-kappa B nuclear translocation. Suppression of DDR1 expression in fibroblasts by siRNA abolished these effects, and an NF-kappa B inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DDR1 up-regulation may occur in other fibroproliferative lung diseases as well.