Alveolar epithelium in pulmonary fibrosis

（申请人的摘要）II型细胞增生是肺肿瘤的标志。 纤维化，但上皮细胞在纤维化过程中的作用是未知的。 虽然已经有许多关于间充质上皮细胞的研究， 在发育中的肺中的相互作用， 成人的肺本项目的目的是定义上皮细胞 间充质相互作用在成人肺，特别是因为它们涉及到 肺纤维化这项提案的大部分重点将放在生物学上。 KGF和TGF-β之间的拮抗作用。KGF是一种重要的生长因子， H细胞并诱导体外分化，而TGF-β抑制 增殖并拮抗KGF对分化的作用。另一 一个主要的问题仍然是正常细胞和 KGF产生的增生II型细胞和增生H型细胞 与纤维化肺病中的增生H型细胞不同。在 共培养正常II型细胞抑制成纤维细胞生长，但 来自纤维化肺的增生II型细胞对成纤维细胞增殖的影响， 不知道。本提案中的体外研究依赖于两种新的培养物 用于大鼠II型细胞维持H型分化功能的系统 细胞一个有顶端通路，另一个有基底外侧通路。在这 我们试图确定（1）是否可以刺激肺泡H型细胞 抑制成纤维细胞增殖，（2）KGF的信号通路 特别是那些导致分化的，（3）KGF和TGF-β的机制 （4）INFY对SP-A和SP-D产生、生长的影响 因子受体表达，以及趋化因子和促纤维化因子的产生 生长因子这些研究旨在确定 肺泡上皮细胞和成纤维细胞以及KGF的作用机制。

(Applicant's Abstract) Type II cell hyperplasia is a hallmark of pulmonary fibrosis, but the role of the epithelium on the fibrotic process is unknown. Although there has been numerous studies on the mesenchymal epithelial interactions in the developing lung, there have been relatively few studies in the adult lung. The purpose of this project is to define the epithelial mesenchymal interactions in the adult lung especially as they relate to pulmonary fibrosis. Much of the focus of this proposal will be on the biologic antagonism between KGF and TGF-beta. KGF is an important growth factor for type H cells and induces differentiation in vitro, whereas TGF-b inhibits proliferation and antagonizes the effects of KGF on differentiation. Another major question that remains are differences between normal cells and hyperplastic type II cells and if hyperplastic type H cells produced by KGF are different from hyperplastic type H cells seen in fibrotic lung disease. In co-culture normal type II cells inhibit fibroblast growth, but the effect of hyperplastic type II cells from fibrotic lung on fibroblast proliferation is not known. The in vitro studies in this proposal rely on two new culture systems for rat type II cells to maintain differentiated function of type H cells. One has apical access and the other basolateral access. In this proposal we seek to determine (1) if alveolar type H cells can be stimulated to inhibit fibroblast proliferation, (2) the signaling pathways for KGF especially those that lead to differentiation, (3) mechanisms for KGF and TGF-b antagonism, and (4) effects of INFY on production of SP-A and SP-D, growth factor receptor expression, and production of chemokines and profibrogenic growth factors. These studies are designed to define the interaction between alveolar epithelial cells and fibroblasts and mechanism of action of KGF.