Fibroblast Specific Protein 1 in Pulmonary Fibrosis

活化的成纤维细胞通过产生胶原和其他基质成分来决定肺纤维化的程度。成纤维细胞特异性蛋白1(FSP1)是S100蛋白超家族的成员，在建立成纤维细胞表型中起早期作用。尽管活化的成纤维细胞在肺纤维化中的来源尚不清楚，但最近对肾脏的研究表明，成纤维细胞可能通过一种称为上皮-间充质转化的现象从上皮细胞产生。转化生长因子-β和其他表型调节剂似乎通过上调FSP1和其他控制成纤维细胞表型的蛋白质来调节这一过程。在这个项目中，我们建议调查以下假设。在肺纤维化中，活化的肺成纤维细胞既来自呼吸道上皮细胞，也来自常驻的间质成纤维细胞。FSP1是这种细胞表型的标志和重要决定因素。FSP1表达细胞的出现和持续时间是判断肺纤维化程度的关键。我们提出了三个具体的目标：1)确定FSP1+细胞在实验性肺纤维化中的作用；2)确定肺上皮-间充质转化是否发生并参与小鼠肺纤维化；3)调节FSP1的表达，确定其在上皮-间充质转化和诱导肺纤维化中的作用。在肺中识别更有用的成纤维细胞标志物将允许在纤维形成刺激后识别和监测这一细胞群，并可能促进靶向治疗，改变表现成纤维细胞表型的细胞的积累或功能。此外，我们计划探索实验性肺纤维化中肺成纤维细胞的起源，希望在这些模型中确定肺上皮-间充质转化的存在和程度将导致创新的干预措施来抑制或逆转这种转化，从而限制纤维化和肺功能障碍。

Activated fibroblasts determine the extent of pulmonary fibrosis by their production of collagen and other matrix components. Fibroblast specific protein 1 (FSP1) is a member of the S100 protein superfamily and appears to play an early role in establishing the fibroblast phenotype. Although the origin of activated fibroblasts in pulmonary fibrosis is uncertain, recent studies in the kidney have shown that fibroblasts may arise from epithelium through a phenomenon called epithelial- mesenchymal transformation. Transforming growth factor-beta and other phenotypic modulators appear to regulate this process through up- regulation of FSP1 and other proteins that control fibroblast phenotype. In this project, we propose to investigate the following hypothesis. In lung fibrosis, activated lung fibroblasts are derived from airway epithelial cells as well as from resident interstitial fibroblasts. FSP1 is both a marker and important determinant of this cellular phenotype. The appearance and persistence of FSP1 expressing cells are crucial for determining the extent of lung fibrosis. We propose three specific aims: 1) to identify the role of FSP1+ cells in experimental lung fibrosis, 2) to determine whether epithelial-mesenchymal transformation occurs in the lungs and contributes to lung fibrosis in the mouse, 3) to modulate FSP1 expression and determine the effects on epithelial-mesenchymal transformation and induction of lung fibrosis. Identification of a more useful fibroblast marker in the lungs would allow identification and monitoring of this cell population after fibrogenic stimuli and could foster targeted treatments that alter the accumulation or function of cells exhibiting the fibroblast phenotype. In addition, we plan to explore the origins of lung fibroblasts in experimental lung fibrosis with the hope that determining the presence and extent of epithelial-mesenchymal transformation in the lungs in these models will lead to innovative interventions to inhibit or reverse this transformation, thus limiting fibrosis and lung dysfunction.