Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor.
Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor.
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DOI：
10.1152/ajplung.00243.2013
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发表时间：
2014-04
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影响因子：
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通讯作者：
Jibing Yang;Miranda Velikoff;E. Canalis;J. Horowitz;Kevin K. Kim
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作者：
Jibing Yang;Miranda Velikoff;E. Canalis;J. Horowitz;Kevin K. Kim
纤维化涉及活化的成纤维细胞的病理性积累和广泛的基质重塑。促纤维化细胞因子，如TGF-β，刺激成纤维细胞过度表达纤维化基质蛋白并诱导促纤维化细胞因子的进一步表达，导致进行性纤维化。结缔组织生长因子（CTGF）是一种促纤维化细胞因子，其指示成纤维细胞活化。上皮细胞在正常肺中是丰富的，但它们对纤维化的贡献仍然不清楚。促纤维化细胞因子可以激活具有与活性成纤维细胞的功能重叠的蛋白质表达和功能的上皮细胞。我们发现，在体外经历TGF-β介导的间质转化的肺泡上皮细胞也能够通过产生CTGF激活肺成纤维细胞。通过抑制Rho信号传导，肺泡上皮细胞CTGF表达显著降低。CTGF报告小鼠在体内博莱霉素后急性肺上皮细胞显示CTGF启动子活性增加。此外，肺上皮细胞特异性CTGF缺失的小鼠对博来霉素的纤维化反应减弱。这些研究提供了直接的证据，即上皮细胞活化在进行性纤维化过程中启动了纤维化效应细胞活化的循环。靶向上皮细胞产生CTGF的治疗提供了一种新的途径来消除这种进行性周期并限制组织纤维化。
Fibrogenesis involves a pathological accumulation of activated fibroblasts and extensive matrix remodeling. Profibrotic cytokines, such as TGF-β, stimulate fibroblasts to overexpress fibrotic matrix proteins and induce further expression of profibrotic cytokines, resulting in progressive fibrosis. Connective tissue growth factor (CTGF) is a profibrotic cytokine that is indicative of fibroblast activation. Epithelial cells are abundant in the normal lung, but their contribution to fibrogenesis remains poorly defined. Profibrotic cytokines may activate epithelial cells with protein expression and functions that overlap with the functions of active fibroblasts. We found that alveolar epithelial cells undergoing TGF-β-mediated mesenchymal transition in vitro were also capable of activating lung fibroblasts through production of CTGF. Alveolar epithelial cell expression of CTGF was dramatically reduced by inhibition of Rho signaling. CTGF reporter mice demonstrated increased CTGF promoter activity by lung epithelial cells acutely after bleomycin in vivo. Furthermore, mice with lung epithelial cell-specific deletion of CTGF had an attenuated fibrotic response to bleomycin. These studies provide direct evidence that epithelial cell activation initiates a cycle of fibrogenic effector cell activation during progressive fibrosis. Therapy targeted at epithelial cell production of CTGF offers a novel pathway for abrogating this progressive cycle and limiting tissue fibrosis.