The present application seeks to determine the effects of transforming growth factor alpha (TGFalpha) on the inflammatory response to lung injury. TGFalpha is a protein found throughout lung development where it is produced by most cells in the lung and binds exclusively to the epidermal growth factor receptor (EGF-R). Transgenic mice expressing human TGFalpha in distal lung using the SP-C promoter demonstrate increased survival and reduced inflammation compared with wild type (wt) controls following acute lung injury caused by exposure to heated Teflon ultrafine particles (UFP). The present application tests the hypothesis that TGFalpha reduces the inflammatory response in acute lung injury. To directly determine the role of TGFalpha in vivo, we will administer TGFalpha to wt mice intraperitoneally, intratracheally, and through adenoviral gene vectors before and during UFP exposure and assess the degree of lung inflammation and injury compared with untreated controls. To determine the mechanisms of TGFalpha's anti-inflammatory properties we will determine TGFalpha's effects on the expression of inflammatory mediators, antioxidant enzyme activity, and cellular sites of proliferation and apoptosis following injury. To determine the cellular compartments required for TGFalpha's effects on inflammation, we will compare the inflammatory response following UFP exposure in mice with deficiency of EGF-R signaling in type II cells only, to mice with deficiency of EGF-R signaling in all cells. This application will determine the role and delineate mechanisms by which TGFalpha reduces lung damage and inflammation following injury, and may be of future value in treating and preventing clinically significant acute lung injury. The principal investigator (PI) for this proposal has completed a fellowship in pediatric pulmonary medicine and is beginning his first year as an Assistant Professor in the Divisions of Pulmonary Medicine and Biology with greater than 75 percent effort in basic research. Throughout his training he has demonstrated a continued interest and ability to accomplish basic science investigation as indicated in his publications. The RCA will allow the PI to continue to develop in the Division of Pulmonary Biology at Children's Hospital directed by Dr. Jeff Whitsett. The Pulmonary Biology Division consists of a highly interactive group of independent senior investigators with funded research efforts in surfactant biology, lung development, mechanisms of lung injury, and cystic fibrosis. The experiments proposed will permit the P.I. to develop an independent line of research in a division dedicated to understanding the basic pathobiology of various lung diseases.
