TGF-ALPHA AND THE EGF RECEPTOR AND ALVEOLAR REPAIR

这一建议概述了一项调查的作用， 生长因子-α（TGF-α），巨噬细胞的趋化因子， 上皮细胞，以及上皮和间充质细胞的有丝分裂原， 细胞，在急性肺损伤的纤维增殖反应。 的 中心假设是TGF-α的表达和 表皮生长因子（EGF）受体在肺损伤区域起着重要作用， 胶原蛋白在调节细胞增殖中的重要作用 修复过程中的积累。 具体的假设是 结论：1）肺泡巨噬细胞和单核细胞表达TGF-α， 受肺损伤部位释放的细胞因子调节; 2）TGF-α 这些细胞的表达通过自诱导机制被放大 通过EGF受体介导; 3）增加TGF-α mRNA水平 在活化的巨噬细胞和单核细胞中观察到的，部分是由于 mRNA稳定性增加; 4）TGF-α表达在 肺急性损伤;和5）细胞增殖，胶原 纤维化细胞因子和生长因子的积累和表达 在TGF-α缺乏的动物中，对肺损伤的反应减少。 目的1是表征TGF-α基因表达的调控， 肺泡巨噬细胞和单核细胞的蛋白分泌。 研究是 计划确定肺区域释放的细胞因子的影响， TGF-α基因转录和蛋白分泌损伤 巨噬细胞和单核细胞，以评估TGF-α mRNA的稳定性， TGF-α基因条件培养基的调节。 这些研究 期望描绘出调节细胞凋亡的分子和细胞机制， 巨噬细胞表达TGF-α。 目的二是明确TGF-β 1在肿瘤细胞中的作用。 α调节细胞增殖、胶原蛋白积累和 细胞因子在博莱霉素诱导的肺损伤修复反应中的表达 TGF-α无效突变转基因和野生基因型小鼠中的损伤。 目的 3是评估患有糖尿病的患者中TGF-α的转录和分泌， 弥漫性急性肺损伤（ARDS）和博莱霉素损伤大鼠。 这些 计划进行研究以确定这些细胞中存在的TGF-α活性。 灌洗液，并确定细胞的位置和分布 TGF-α和EGF受体在肺损伤中的作用 这些研究 预期描述肺损伤后TGF-α的表达， 并提供一个框架， 在博来霉素损伤的大鼠和具有纤维增生的转基因小鼠中， 这是人类急性肺损伤中发生的一种反应。 的最终目标 这一建议是为研究奠定必要的基础 涉及TGF-α表达的治疗性操作和/或 EGF受体激活，促进肺泡修复。

This proposal outlines an investigation of the role of transforming growth factor-alpha (TGF-alpha), a chemotactic factor for macrophage and epithelial cells, as well as, a mitogen for epithelial and mesenchymal cells, in the fibroproliferative response to acute lung injury. The central hypothesis is that expression of TGF-alpha and activation of the epidermal growth factor (EGF) receptor in areas of lung injury plays an important role in modulating cellular proliferation an collagen accumulation during the reparative process. The specific hypotheses are that: 1) TGF-alpha expression by alveolar macrophage and monocytes is regulated by cytokines released at sites of lung injury; 2) TGF-alpha expression by these cells is amplified by an auto-induction mechanism mediated through the EGF receptor; 3) the increased TGF-alpha mRNA levels observed in activated macrophage and monocytes is due, in part, to increased mRNA stability; 4) TGF-alpha expression is increased in the lung following acute injury; and 5) cellular proliferation, collagen accumulation and expression of fibrogenic cytokines and growth factors in response to lung injury is diminished in TGF-alpha deficient animals. Aim 1 is to characterize the regulation of TGF-alpha gene expression and protein secretion by alveolar macrophage and monocytes. Studies are planned to determine the effects of cytokines released in areas of lung injury of TGF-alpha gene transcription and protein secretion by macrophage and monocytes, to evaluate TGF-alpha mRNA stability and regulation of TGF-alpha gene conditioned medium. These studies are expected to delineate molecular and cellular mechanisms that regulate macrophage expression of TGF-alpha. Aim 2 is to define the role of TGF- alpha regulating cellular proliferation, collagen accumulation and cytokine expression in the reparative response to bleomycin induced lung injury in TGF-alpha null mutation transgenic and wild genotype mice. Aim 3 is to evaluate TGF-alpha transcription and secretion in patients with diffuse acute lung injury (ARDS) and bleomycin injured rats. These studies are planned to determine TGF-alpha activity present in these lavage fluids, and to identify the cellular location and distribution of TGF-alpha and the EGF receptor in injured lung. These studies are expected to delineate expression of TGF-alpha following lung injury in humans and to provide a framework for correlating the observations made in bleomycin injured rats and transgenic mice with the fibroproliferative response that occurs in human acute lung injury. the ultimate goal of this proposal is to establish the necessary foundation for research directed toward therapeutic manipulation of TGF-alpha expression and/or EGF receptor activation, facilitating alveolar repair.