Interstitial lung disease (ILD) encompasses a broad group of inflammatory and immune diseases which are characterized by chronic alveolitis, interstitial thickening and fibrosis. ILD includes hypersensitivity pneunonitis, sarcoidosis, idiopathic pulmonary fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, as well as disease associated ILD in systemic lupus erythematosus. Although ILD is caused by a wide variety of immunologic, pollutant and infectious agents and mechanisms, the constant hallmark of ILD is the presence of inflammatory and immune cells (neutrophils, macrophages, and lymphocytes) within the lung tissue. It is clear that much of the tissue damage that occurs in ILD is related to the consequences of the recruitment and accumulation of these inflammatory and immune cells into lung tissue. Thus the control of the accumulation of these inflammatory cells within the lung tissue plays a major role in both acute andchronic stages of ILD as well as other lung diseases. The accumulation of the inflammatory cells is dependent on the generation of chemotactic factors within the lung. Although these chemotactic factors may arise from humoral systems (such as complement) or from the lung itself (alveolar macropahges, type II pneumocytes or other lung cells), it is clear that the presence of chenotactic factors within the lung is pivotal to the recruitment of inflammatory cells into the lung. Thus, delineating the sources, nature and production of chemotactic factors and precursors (such as fifth component of complement) within the lung will provide important insights into the underlying mechanisms of ILD, as well as other lung diseases. To achieve these goals we propose to: 1)determine the mechanisms by which preformed chemotactic factors (chemotactic factors derived from the fifth component complement (C5fr) induce lung inflammation, 2) determine the mechanisms of C5 induced lung inflammation, 3) determine the sources and subpopulations of C5 sereting lung cells in normal and injured experimental animals, and 4) correlate the role of lung derived chemotactic factors and complement components (C5) in both experimental and human inflammatory lung disease. By a rigorous and careful exploration of the sources and mechanisms of action of chemotactic factors and C5 in lung inflammation we will obtain data which will have a direct application to the problems of interstitial lung disease specifically and inflammatory lung disease in general.
