TGF-ALPHA AND THE EGF RECEPTOR AND ALVEOLAR REPAIR

这项提案概述了对转型的作用的调查 巨噬细胞趋化因子--生长因子-α 上皮细胞以及上皮和间充质的有丝分裂原 细胞，在急性肺损伤的纤维增生性反应中。这个 中心假设是转化生长因子-α的表达和血管内皮细胞的激活 表皮生长因子受体在肺损伤区域的作用 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 提示：1)肺泡巨噬细胞和单核细胞表达转化生长因子-α 由肺损伤部位释放的细胞因子调节；2)转化生长因子-α 这些细胞的表达是通过自动诱导机制放大的 通过EGF受体介导；3)升高的转化生长因子-αmRNA水平 在激活的巨噬细胞和单核细胞中观察到的部分原因是 4)转化生长因子-α的表达增加。 急性损伤后肺；5)细胞增殖、胶原 致纤维化细胞因子和生长因子的积聚和表达 在转化生长因子-α缺乏的动物中，对肺损伤的反应减弱。 目的1研究转化生长因子-α基因表达的调控机制。 肺泡巨噬细胞和单核细胞分泌蛋白质。研究是 计划确定在肺部区域释放的细胞因子的影响 三七总皂甙对转化生长因子-α基因转录和蛋白分泌的损伤 巨噬细胞和单核细胞，以评价转化生长因子-αmRNA的稳定性和 转化生长因子-α基因条件培养液的调控。这些研究是 有望描述调控的分子和细胞机制 巨噬细胞表达转化生长因子-α。目标2是确定转化生长因子-2的作用 α-调节细胞增殖、胶原堆积和 细胞因子在博莱霉素性肺损伤修复反应中的表达 转化生长因子α零突变转基因和野生型小鼠的损伤。目标 3研究目的是评估慢性阻塞性肺疾病患者的转化生长因子-α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转化生长因子-α活性 灌洗液，并确定细胞的位置和分布 肺损伤后肺组织中转化生长因子-α和EGF受体的表达这些研究是 有望描述肺损伤后转化生长因子-α的表达 并提供一个框架，将所作的观察结果相互关联 博莱霉素损伤大鼠和纤维增殖物转基因小鼠的实验研究 在人类急性肺损伤中发生的反应。的最终目标是 这项建议是为了为研究奠定必要的基础 针对转化生长因子-α的表达和/或治疗操作 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.