Evidence exists which implicates an immunologic mechanism in the pathogenesis of pulmonary fibrosis. Whether the immune response is a major contributor in the pathogenesis of pulmonary fibrosis or is just a secondary manifestation of lung injury is not known. The purpose of this proposal is to further investigate the role of immune mechanisms in the pathogenesis of diffuse fibrosing pulmonary disorders. A bleomycin animal model of pulmonary fibrosis which morphologically and physiologically resembles human diffuse pulmonary fibrosis will be used. Lymphocyte populations will be characterized and isolated from the lungs of bleomycin animals at various stages of the fibrotic mechanism. The effect of these immune cells and their supernates upon fibroblast growth, collagen synthesis (total collagen and ratio of type I to type III) and prostaglandin elaboration will be studied. Since in vivo experiments in our laboratory have shown that thymectomized animals and animals treated with indomethacin, methylprednisolone, cobra venom factor, anti-neutrophil serum and anti-lymphocyte globulin have an altered fibrotic response in this animal model system, we will also study immune cell populations from these treated animals to see if their effect on fibroblast activity is different from untreated animals. Mononuclear cells will be purified from spleen, bronchoalyeolar lavage and lung from both normal animals and animals at various times during the development of bleomycin-induced pulmonary fibrosis. With the use of specific antibodies to subpopulations of lymphocytes and the fluorescence-activated cell sorter the following populations of mononuclear cells will be isolated: macrophages (normal and post bleomycin), B-cells and their subpopulations (Thyl+, Ig+ and Thyl-, Ig+), T-cells and their subpopulations (helper cell activity - W3/25+ cells and suppressor cell activity - 0X8+ cells). The effect of supernates obtained from short term culture of these purified cell populations on fibroblasts cultured from normal lungs and lungs at various stages during the development of pulmonary fibrosis will be studied. To better correlate our in vitro results with in vivo phenomena, cell transfer experiments will be performed. Cell populations which influence fibroblast activity in vitro will be used in transfer experiments to see if their effect can also be detected in vivo. Further, T-cells purified as stated above will be cloned for both nonspecific and specific clonal responsiveness. T-cell clones which arise will be analyzed in the same manner as other purified cell populations. The significance of this proposal lies in its direct approach to analyze whether immune cells can directly influence fibroblast activity.
| Grunze, M F; Parkinson, D; Sulavik, S B et al. (1988) Effect of corticosteroids on lung volume-pressure curves in bleomycin-induced lung injury in the rat. Exp Lung Res 14:183-95 |
| Thrall, R S; Swendsen, C L; Shannon, T H et al. (1987) Correlation of changes in pulmonary surfactant phospholipids with compliance in bleomycin-induced pulmonary fibrosis in the rat. Am Rev Respir Dis 136:113-8 |
