Integrin α4β1 regulates migration across basement membranes by lung fibroblasts
Integrin α4β1 regulates migration across basement membranes by lung fibroblasts
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DOI：
10.1164/rccm.200301-041oc
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发表时间：
2003-08-15
影响因子：
24.7
通讯作者：
Arenberg, DA
中科院分区：
文献类型：
--
作者：
White, ES;Thannickal, VJ;Arenberg, DA
特发性肺纤维化是一种以肺远端气隙中的成纤维细胞积聚和活化为特征的疾病。我们假设纤维化肺成纤维细胞通过整合素介导的机制迁移/侵入基底膜作为进入肺泡的手段。我们证明，在来自特发性肺纤维化患者的肺成纤维细胞中，纤连蛋白信号传导是基底膜迁移/侵入基底膜的必要和充分条件。这种作用是通过α（5）β（1）整联蛋白介导的，因为纤连蛋白-α（5）整联蛋白连接的阻断减弱了这种反应。相反，α 4 β 1整合素的连接抑制正常肺成纤维细胞对基底膜的侵袭，但不抑制纤维化肺成纤维细胞的侵袭。这种表型差异与α 4 β 1整合素的表面表达无关，如流式细胞术所示。在正常的肺成纤维细胞中，而不是在纤维化的肺成纤维细胞中，我们发现α（4）β（1）整合素的连接诱导了10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）活性的显着增加。与正常肺成纤维细胞相比，纤维化肺成纤维细胞表达组成性较少的PTEN mRNA和蛋白以及磷酸酶活性。总之，这些数据表明，通过PTEN的α（4）β（1）信号传导的损失赋予纤维化肺成纤维细胞迁移/侵袭表型。此外，这项研究暗示了在特发性肺纤维化的病理生理学中PTEN功能的丧失。
Idiopathic pulmonary fibrosis is a disease that is characterized by fibroblast accumulation and activation in the distal airspaces of the lung. We hypothesized that fibrotic lung fibroblasts migrate/invade across basement membranes by integrin-mediated mechanisms as a means of entering alveoli. We demonstrate that in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis, fibronectin signaling is both necessary and sufficient for basement membrane migration/invasion across basement membranes. This effect is mediated through the alpha(5)beta(1), integrin because blockade of fibronectin-alpha(5) integrin ligation attenuated this response. In contrast, ligation of alpha(4)beta(1) integrin inhibits basement membrane invasion by normal lung fibroblasts but not by fibrotic lung fibroblasts. This phenotypic difference is not related to surface expression of the (alpha(4)beta1 integrin, as demonstrated by flow cytometry. In normal lung fibroblasts but not in fibrotic lung fibroblasts, we show that ligation of alpha(4)beta(1) integrin induces a significant increase in phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activity. Fibrotic lung fibroblasts express constitutively less PTEN mRNA and protein as well as phosphatase activity in comparison to normal lung fibroblasts. Together, these data suggest that a loss of alpha(4)beta(1) signaling via PTEN confers a migratory/invasive phenotype to fibrotic lung fibroblasts. Furthermore, this study implicates a loss of PTEN function in the pathophysiology of idiopathic pulmonary fibrosis.