Alveolar epithelium in pulmonary fibrosis

(申请人摘要)II型细胞增生是肺部疾病的一个标志 纤维化，但上皮细胞在纤维化过程中的作用尚不清楚。 虽然已经有很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，相对较少的研究 成人的肺。这个项目的目的是定义上皮细胞 成人肺内间充质的相互作用，尤其是当它们与 肺纤维化。这项提案的大部分焦点将放在生物学上 KGF与转化生长因子-β的拮抗作用。KGF是一种重要的类风湿因子 并在体外诱导分化，而转化生长因子-b则抑制 并拮抗KGF对细胞分化的影响。另一个 剩下的主要问题是正常细胞和正常细胞之间的差异 KGF产生的增生型II型细胞和IF增生型H型细胞 不同于纤维化肺部疾病中见到的增生型H细胞。在……里面 共培养的正常II型细胞抑制成纤维细胞的生长，但 纤维化肺来源的增生型II型细胞对成纤维细胞增殖的影响 不知道。这项提案中的体外研究依赖于两种新的培养方式 大鼠II型细胞维持H型分化功能的系统 细胞。一种是根尖通路，另一种是基底外侧通路。在这 我们试图确定(1)肺泡型H细胞是否能被刺激 抑制成纤维细胞增殖；(2)KGF的信号转导途径 尤其是那些导致分化的基因；(3)KGF和转化生长因子-β的作用机制 拮抗作用；(4)INFY对SP-A和SP-D产生及生长的影响 因子受体的表达、趋化因子和促纤维化因子的产生 增长因素。这些研究的目的是定义 肺泡上皮细胞和成纤维细胞及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.