Multiple lines of evidence support an import role for the insulin-like growth factors, IGF-I and IGF-II, their receptors and binding proteins in lung development and repair following injury. Recent studies have demonstrated that IGF-I prevents cell death in several cell types and IGFs and IGF binding proteins (IGFBPs) change in response to tissue injury. We hypothesize that IGF-I acts similarly in lung and is important for lung epithelial cell survival and repair following injury by infection or toxic environmental agents. We, therefore, propose to better define the role of the IGF system in maintenance and repair of airway epithelium and to examine the potential of IGF-I to improve cell survival following airway epithelium injury. We will first determine the role of the IGFs, their receptors, and binding proteins in normal growth and differentiation of airway epithelium using Northern hybridization, in situ hybridization, and immunohistochemical analyses in large airways of adult rat, ferret and mouse. Next, the effect of exogenous IGF-I on airway epithelial proliferation and differentiation will be examined with a transgenic mouse line, SPC/IGF, that expresses IGF-I in distal lung epithelium under the control of the promoter for the surfactant associated protein C gene and with instilled IGF-I into airways of adult animals. To examine the potential of IGF-I to promote airway epithelial cell survival after injury, the transgenic SPC/IGF mouse line and adult rat, ferret, and mouse will be subjected to various airway injuries including viral infection, hyperoxia, and exposure to sulfur dioxide. Finally, we propose to examine the interaction of the IGFs, their receptors and binding proteins with inflammatory mediators produced by airway epithelium infected with respiratory viruses. The potential of direct inflammatory mediator interaction with IGF-I gene expression will be examined using the 5' flanking DNA of the IGF gene fused to a luciferase reporter gene. Results from these studies will better define the role of the IGF system in airway development and repair and examine the potential for therapeutic use of IGF-I to reduce injury or promote repair in airway epithelium infected with virus or subjected to environmental toxins.
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