TGF-ALPHA AND THE EGF RECEPTOR AND ALVEOLAR REPAIR

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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.