SCOR IN THE PATHOBIOLOGY OF FIBROTIC LUNG DISEASE

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The long-term objective of this SCOR is to further our understanding of the pathogenesis of idiopathic pulmonary fibrosis (IPF) and sarcoidosis. A clearer understanding of the pathogenesis of these diseases is required to develop new treatment strategies. The central hypothesis for this SCOR proposal is: acquired alterations in parenchymal/stromal cell phenotype create tissue micro environments which steer the progression of tissue remodeling towards progressive fibrosis rather than the restoration of normal alveolar architecture. This change in phenotype results in and is perpetuated by changes in the elaboration of effector molecules which influence the fibrotic process via autocrine and paracrine loops. These altered secretory phenotypes represent potential targets for therapeutic interventions. The specific hypotheses in this SCOR are: 1. Angiogenesis during the pathogenesis of fibroproliferation in interstitial lung disease is dependent on members of the CXC chemokine family acting as either angiogenic or angiostatic factors. The biological balance in expression of these CXC chemokines dictates that neovascularization, in association with fibroproliferation, either regresses or progresses to end-stage pulmonary fibrosis. 2. Diminished prostaglandin E2 (PGE2) synthesis is an important determinant of fibrogenesis and of the phenotypic alterations which characterize fibroblasts obtained from patients with IPF. 3. Fibroblast activation in tissue fibrosis is dependent upon the expression of a specific disease phenotype characterized by the predominance of Th2 type cytokines. 4. Enhancement of fibrolytic activity within the alveolar space using gene transfer technology will reduce the pulmonary fibrosis that accompanies inflammatory lung injury. 5. Alveolar epithelial cells and macrophages participate in a bi- directional paracrine interaction in which AEC-derived GM-CSF leads to the expression of macrophage mediators, such as HGF and uPA that preserve normal alveolar architecture. Furthermore, HGF is required for normal, non-fibrotic healing of the alveolar lining following injury and for the induction of uPA activity in epithelial cells. This SCOR will take a multi-disciplinary approach to testing these hypotheses. The expertise of investigators trained in Internal Medicine, Pathology, Cell and Molecular Biology, Biochemistry, and Biostatistics will be utilized. The strength of this proposal are the investigators long-standing interests in fibrotic lung disease, a proven commitment to collaborative research by both clinicians and basic scientists, access to a large population of IPF and sarcoid patients, and extra-ordinary institutional resources for biomedical research.