Idiopathic Pulmonary Fibrosis (IPF) is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix deposition causing irreversible distortion of lung architecture. The pathogenic mechanisms are largely unknown, but a recently identified hallmark of the pathology in fatal IPF are isolates foci of fibroblasts that acquire smooth muscle-like properties, termed myofibroblasts located at the leading edge of dense collagen interspersed with areas of preserved lung architecture. Progressive fibrosis despite anti-inflammatory therapies have challenged the concept that fibrosis occurs solely as a consequence of unremitting inflammation and has led to the development of new paradigms in pathogenesis. Identification of fibroblastic foci has led to the concept that IPF is a result of an abnormal wound healing response to an exogenous injury. Furthermore, the biology of IPF has been suggested to have parallels with cancer biology including increased angiogenesis, excessive growth factor production and a failure of myofibroblasts to undergo apoptosis. Survivin is a recently identified bifunctional protein that suppresses apoptosis and regulates cell division. It is expressed by most tumors but not in most normal tissues. Survivin expression is cell cycle dependent and requires phosphorylation by Cdc2 kinase to function as an inhibitor of apoptosis. It is upregulated by certain growth factors including VEGF and IGF- 1. Recent studies have suggested that survivin may be an important target in cancer therapy. Our preliminary studies suggest that survivin is exprssed in fibroblastic foci in both IPF and experimental lung fibrosis. This has led us to hypothesize that survivin may regulate the recruitment and maintenance of fibroblastic foci and could be a novel target for therapy of pulmonary fibrosis. We will investigate this hypothesis in the following Specific Aims: 1. Characterize survivin expression in Idiopathic Interstitial Pneumonis. 2. Determine the role of survivin in vivo in the initiation and progression of experimental pulmonary fibrosis. 3. Determine the role of survivin in regulating the IPF fibroblast phenotype in vitro.
