Insulin-like growth factor-II is increased in systemic sclerosis-associated pulmonary fibrosis and contributes to the fibrotic process via Jun N-terminal kinase- and phosphatidylinositol-3 kinase-dependent pathways
Insulin-like growth factor-II is increased in systemic sclerosis-associated pulmonary fibrosis and contributes to the fibrotic process via Jun N-terminal kinase- and phosphatidylinositol-3 kinase-dependent pathways
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DOI：
10.2353/ajpath.2008.071021
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发表时间：
2008-06-01
影响因子：
6
通讯作者：
Feghali-Bostwick, Carol A.
中科院分区：
文献类型：
--
作者：
Hsu, Eileen;Feghali-Bostwick, Carol A.
系统性硬化症（SSc）相关的肺纤维化，其中有几个有效的治疗，是最常见的原因SSc相关的死亡率。我们检测了胰岛素样生长因子（IGF）-II在对照组和SSc患者肺组织中的表达，以确定其在纤维化发病机制中的作用。采用免疫组化法检测体内IGF-II水平。从肺组织培养原代肺成纤维细胞，并使用逆转录-聚合酶链反应测定IGF-II mRNA。Western印迹分析测量细胞外基质（ECM）的产生和磷酸化的信号分子。免疫组化染色显示SSc肺成纤维细胞灶中IGF-II表达增加。此外，与正常肺成纤维细胞相比，原发性SSc肺成纤维细胞IGF-II mRNA增加了4倍，IGF-II蛋白增加了2倍。SSc肺成纤维细胞中的IGF-II mRNA主要由IGF-H基因的P3启动子表达，IGF-II诱导I型胶原和纤连蛋白产生的剂量和时间依赖性增加。IGF-H触发了磷脂酰肌醇-3激酶和Jun N-末端激酶信号级联的激活，其抑制减少了IGF-II诱导的ECM产生。我们的研究表明，增加局部IGF-II表达在SSC相关的肺纤维化在体外和体内，以及IGF-II诱导的ECM生产通过磷脂酰肌醇-3激酶和Jun N-末端激酶依赖性途径。我们的结果提供了新的见解肺纤维化。
Systemic sclerosis (SSc)-related pulmonary fibrosis, for which there are few effective therapies, is the most common cause of SSc-related mortality. We examined insulin-like growth factor (IGF)-II expression in explanted lung tissues from control and SSc patients to determine its role in the pathogenesis of fibrosis. IGF-II levels in vivo were detected using immunohistochemistry. Primary lung fibroblasts were cultured from lung tissues, and IGF-II mRNA was measured using reverse transcriptase-polymerase chain reaction. Western blot analysis measured extracellular matrix (ECM) production and phosphorylated signaling molecules. Immunostaining revealed increased IGF-II expression in fibroblastic foci of SSc lungs. Furthermore, primary SSc lung fibroblasts had a fourfold increase in IGF-II mRNA and a twofold increase in IGF-II protein compared with normal lung fibroblasts. IGF-II mRNA in SSc lung fibroblasts was expressed primarily from the P3 promoter of the IGF-H gene, and IGF-II induced both a dose- and time-dependent increase in collagen type I and fibronectin production. IGF-H triggered the activation of both phosphatidyhnositol-3 kinase and Jun N-terminal kinase signaling cascades, the inhibition of which diminished IGF-II-induced ECM production. Our study demonstrates increased local IGF-II expression in SSc-associated pulmonary fibrosis both in vitro and in vivo as well as IGF-II-induced ECM production through both phosphatidyhnositol-3 kinase- and Jun N-terminal kinase-dependent pathways. our results provide novel insights pulmonary fibrosis.