LUNG REPAIR--ROLE OF TGF-ALPHA, TGF-BETA & PDGF

这项拟议的研究将检验这样一种假设，即转变增长 转化生长因子-α是上皮细胞和间充质细胞的有丝分裂原， 上皮细胞抑制因子转化生长因子-β 细胞增殖和胶原合成的诱导剂，以及血小板- 衍生生长因子(PDGF)是间充质细胞的有丝分裂原，调节 肺损伤后发生的细胞增殖和纤维化。 这些研究将评估成人患者中生长因子的表达 呼吸窘迫综合征及博莱霉素性肺损伤的实验研究 受伤。第一个特定的目标是评估转录和分泌。 肺损伤后肺组织中转化生长因子-α、转化生长因子-β和血小板衍生生长因子的变化。研究正在计划中 测定肺泡巨噬细胞中转化生长因子-α的稳态mRNA水平 α、转化生长因子-β和血小板衍生生长因子的A-链和B-链； 灌洗液和巨噬细胞中转化生长因子-β和血小板衍生生长因子的活性水平 条件培养液；并测定转化生长因子-1的稳态mRNA水平。 损伤肺组织中的α、转化生长因子-β和血小板衍生生长因子。这些研究预计将 描绘这些细胞因子在肺泡室的释放，以 确定肺泡巨噬细胞是否是这些因子的细胞来源 Vivo，NAD检查其他肺实质细胞可能 在肺损伤后表达这些细胞因子。第二个具体目标 重点关注巨噬细胞来源的转化生长因子-α，它可能在 肺修复过程中的肺泡再上皮化。这些研究是 设计用来测定分子大小(S)和细胞加工 巨噬细胞来源的转化生长因子-α基因的时程测定 转录和蛋白分泌；评估转化生长因子-α信息的稳定性 和对转化生长因子-α基因转录的调节；并确定 特异性激动剂和拮抗剂对转化生长因子-α基因表达的影响 人外周血单核细胞和肺泡巨噬细胞。

The proposed research will examine the hypothesis that Transforming Growth Factor-alpha (TGF-alpha), a mitogen for epithelial and mesenchymal cells, Transforming Growth Factor - beta (TGF-beta), an inhibitor of epithelial cell proliferation and an inducer of collagen synthesis, and Platelet- derived Growth Factor (PDGF) a mitogen for mesenchymal cells, regulate the cellular proliferation and fibrosis that occurs following lung injury. These studies will evaluate growth factor expression in patients with Adult Respiratory Distress Syndrome and in rabbits with bleomycin-induced lung injury. The first Specific Aim is to evaluate transcription and secretion of TGF-alpha, TGF-beta and PDGF following lung injury. Studies are planned to determine steady-state mRNA levels in alveolar macrophages for TGF- alpha, TGF-beta and the A- and B- chains of PDGF; to determine TGF-alpha, TGF-beta and PDGF activity levels in lavage fluid and macrophage conditioned medium; and to determine steady-state mRNA levels for TGF- alpha, TGf-beta and PDGF in injured lung. These studies are expected to delineate the release of these cytokines in the alveolar compartment, to determine if alveolar macrophages are a cellular source of these factors in vivo, nad to examine the possibility that other lung parenchymal cells may express these cytokines following lung injury. The second Specific Aim focuses upon macrophage-derived TGF-alpha which may play a crucial role in alveolar reepithelialization during lung repair. These studies are designed to determine the molecular size(s) and cellular processing of macrophage-derived TGF-a; to determine the time course of TGF-a gene transcription and protein secretion; to evaluate TGF-a message stability and the regulation of TGF-a gene transcription; and to determine the effects of specific agonists and antagonists on TGF-a gene expression by human peripheral blood monocytes and alveolar macrophages.