Genomic profile of matrix and vasculature remodeling in TGF-α-Induced pulmonary fibrosis
Genomic profile of matrix and vasculature remodeling in TGF-α-Induced pulmonary fibrosis
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DOI：
10.1165/rcmb.2006-0455oc
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发表时间：
2007-09-01
影响因子：
6.4
通讯作者：
Leikauf, George D.
中科院分区：
文献类型：
--
作者：
Hardie, William D.;Korfhagen, Thomas R.;Leikauf, George D.
转化生长因子a的表达。转基因小鼠呼吸道上皮细胞中的TGF-α会导致肺纤维化、恶病质、肺动脉高压和肺功能改变。为了鉴定介导肺重塑的基因和分子途径，在 TGF-α 表达后多次进行 mRNA 微阵列分析，并揭示了与 TGF-α 在细胞外基质和血管生成调节中的作用一致的变化。细胞外基质蛋白的转录本与先前确定在肺纤维化中起作用的基因转录本一起增加，包括生腱蛋白 C、骨桥蛋白和丝氨酸（或半胱氨酸）消化酶抑制剂、clacle F、成员 1。调节血管过程的转录本包括 B 型内皮素受体、内皮特异性受体酪氨酸激酶和小窝蛋白、小窝蛋白 1 减少。当不再诱导 TGF-α 表达时，肺重塑部分逆转，肺功能和肺动脉高压恢复正常。解析期间增加的转录物包括中期因子、基质金属蛋白酶 2 和溶血补体。层次聚类显示，TGF-α 调节的基因与特发性肺纤维化患者肺部改变的基因相似。这些研究支持上皮细胞衍生的 TGF-α 在调节改变气道和血管结构和功能的过程中的作用。
Expression of transforming growth factor a. (TGF-alpha) in the respiratory epithelium of transgenic mice caused pulmonary fibrosis, cachexia, pulmonary hypertension, and altered lung function. To identify genes and molecular pathways mediating lung remodeling, mRNA microarray analysis was performed at multiple times after TGF-alpha expression and revealed changes consistent with a role for TGF-alpha in the regulation of extracellular matrix and vasculogenesis. Transcripts for extracellular matrix proteins were augmented along with transcripts for genes previously identified to have roles in pulmonary fibrosis, including tenascin C, osteopontin, and serine (or cysteine) pepticlase inhibitor, clacle F, member 1. Transcripts regulating vascular processes including endothelin receptor type B, endothelial-specific receptor tyrosine kinase, and caveolin, caveolae protein 1 were decreased. When TGF-alpha expression was no longer induced, lung remodeling partially reversed and lung function and pulmonary hypertension normalized. Transcripts increased during resolution included midkine, matrix metalloproteinase 2, and hemolytic complement. Hierarchical clustering revealed that genes regulated by TGF-alpha were similar to those altered in the lungs of patients with idiopathic pulmonary fibrosis. These studies support a role for epithelial cell-derived TGF-alpha in the regulation of processes that alter the airway and vascular architecture and function.