Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis.
Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis.
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DOI：
10.1084/jem.20080001
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发表时间：
2008-07-07
期刊：
影响因子：
--
通讯作者：
Henke C
中科院分区：
文献类型：
--
作者：
Xia H;Diebold D;Nho R;Perlman D;Kleidon J;Kahm J;Avdulov S;Peterson M;Nerva J;Bitterman P;Henke C
特发性肺纤维化（IPF）是一种持续进展的肺部疾病，其中成纤维细胞在I型富胶原基质内积聚在肺泡壁。尽管来自IPF患者的肺成纤维细胞在增殖功能上表现出持久的病理改变，但区分IPF成纤维细胞与正常成纤维细胞的分子机制仍然未知。聚合型胶原通常抑制成纤维细胞增殖，为组织损伤后限制纤维增殖提供了生理机制。我们证明β1整合素与聚合胶原的相互作用通过抑制磷酸肌醇3-激酶(PI3K) -Akt-S6K1信号通路抑制正常成纤维细胞增殖，这是由于维持肿瘤抑制磷酸酶和紧张素同源物（PTEN）的高磷酸酶活性。相比之下，IPF成纤维细胞避开了这种抑制，表现出β1整合素信号通路的病理模式，以响应聚合胶原，导致PI3K-Akt-S6K1信号通路的异常激活，这是由PTEN活性不适当的低引起的。PTEN缺失小鼠在组织损伤后表现出延长的纤维增殖反应，IPF肺组织的免疫组化分析显示纤维化灶内细胞中Akt的活化。这些结果为IPF成纤维细胞增殖途径的缺陷负调控提供了直接证据，并支持IPF的发病机制涉及内在成纤维细胞缺陷的理论。
Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease in which fibroblasts accumulate in the alveolar wall within a type I collagen–rich matrix. Although lung fibroblasts derived from patients with IPF display durable pathological alterations in proliferative function, the molecular mechanisms differentiating IPF fibroblasts from their normal counterparts remain unknown. Polymerized type I collagen normally inhibits fibroblast proliferation, providing a physiological mechanism to limit fibroproliferation after tissue injury. We demonstrate that β1 integrin interaction with polymerized collagen inhibits normal fibroblast proliferation by suppression of the phosphoinositide 3-kinase (PI3K)–Akt–S6K1 signal pathway due to maintenance of high phosphatase activity of the tumor suppressor phosphatase and tensin homologue (PTEN). In contrast, IPF fibroblasts eluded this restraint, displaying a pathological pattern of β1 integrin signaling in response to polymerized collagen that leads to aberrant activation of the PI3K–Akt–S6K1 signal pathway caused by inappropriately low PTEN activity. Mice deficient in PTEN showed a prolonged fibroproliferative response after tissue injury, and immunohistochemical analysis of IPF lung tissue demonstrates activation of Akt in cells within fibrotic foci. These results provide direct evidence for defective negative regulation of the proliferative pathway in IPF fibroblasts and support the theory that the pathogenesis of IPF involves an intrinsic fibroblast defect.
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