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

拟议的研究将检验这一假设，即转型增长 α因子（TGF-α），一种上皮细胞和间充质细胞的有丝分裂原， 转化生长因子-β（TGF-β），一种上皮细胞增殖抑制剂， 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）是间充质细胞的促分裂原，调节细胞增殖， 肺损伤后发生的细胞增殖和纤维化。 这些研究将评估成人乳腺癌患者中生长因子的表达。 博莱霉素致肺损伤家兔呼吸窘迫综合征的实验研究 损伤 第一个具体目标是评估转录和分泌 TGF-α、TGF-β和PDGF在肺损伤后的变化。 计划进行研究 测定肺泡巨噬细胞中TGF-β的稳态mRNA水平， TGF-α，TGF-β和PDGF的A-和B-链;为了测定TGF-α， 灌洗液和巨噬细胞中TGF-β和PDGF活性水平 条件培养基;并测定TGF-β 1的稳态mRNA水平。 TGF-α、TGF-β和PDGF在损伤肺中的表达。 这些研究预计将 描绘这些细胞因子在肺泡室中的释放， 确定肺泡巨噬细胞是否是这些因子的细胞来源， 体内，并检查其他肺实质细胞可能 表达这些细胞因子。 第二个具体目标 主要关注巨噬细胞来源的TGF-α，它可能在 肺修复过程中的肺泡上皮再生。 这些研究 设计用于确定分子大小和细胞加工， 巨噬细胞来源的TGF-α;以确定TGF-α基因表达的时间过程 转录和蛋白质分泌;评估TGF-α信使稳定性 和TGF-α基因转录的调节;并确定TGF-α基因的转录水平。 特异性激动剂和拮抗剂对TGF-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.