EPITHELIAL GROWTH FACTORS IN ENVIRONMENTAL LUNG DISEASE

描述：该提案侧重于吸入的分子机制， 无机颗粒诱导的纤维增生性肺病（FLD）。的 正在研究的中心假设是间质性纤维化肺 疾病是由间充质细胞生长因子，PDGF，TGF-α， TGF-β和TNF-α，它们是由细胞合成和分泌的。 肺损伤导致细支气管肺泡上皮细胞。四个具体 目的是测试这个假设。在aim 1中，两种小鼠 抵抗吸入石棉的纤维化作用的药物被用于 确定基因和生长的时间和解剖表达 肺泡上皮细胞的因子与阻力相关。在aim 2中 从这些相同的小鼠品系中分离肺泡上皮细胞， 确定石棉抗性表型是否在体外保持。在 目的3：主要研究者建议将重点放在PCNA表达， 能够形成纤维化病变的细胞与来自耐药细胞的细胞 小鼠品系。在aim 4转基因小鼠中， 细支气管肺泡上皮和自发发育 肺中的纤维增生异常将与 石棉抗性菌株，以确定是否有后代增加 对石棉的敏感性这可能与PDGF-B在肺纤维化中的作用有关 并针对该生长因子进行抗体或基因治疗。

DESCRIPTION: This proposal focuses on the molecular mechanisms for inhaled inorganic particle-induced fibroproliferative lung disease (FLD). The central hypothesis being examined is that interstitial fibrogenic lung disease is mediated by the mesenchymal cell growth factors, PDGF, TGF-alpha, TGF-beta and TNF-alpha, that are synthesized and secreted by the bronchiolar-alveolar epithelium as a result of lung injury. Four specific aims are given to test this hypothesis. In aim 1, two strains of mice resistant to the fibrogenic effects of inhaled asbestos are used to determine if the temporal and anatomic expression of the genes and growth factors by the alveolar epithelium correlates with resistance. In aim 2 alveolar epithelial cells are isolated from these same mice strains to determine if the asbestos-resistance phenotype is maintained in vitro. In aim 3 the principal investigator proposes to focus on PCNA expression in cells capable of forming fibrogenic lesions versus those from resistant mouse strains. In aim 4 transgenic mice overexpressing human PDGF-B within the bronchiolar-alveolar epithelium and spontaneously developing fibroproliferative abnormalities in the lung will be crossed with asbestos-resistant strains to determine if the offspring have increased susceptibility to asbestos. This would implicate PDGF-B in fibrogenic lung disease and target this growth factor for antibody or gene therapy.