The diffuse interstitial lung diseases (ILD) remain important clinical problems largely of unknown pathogenesis and often associated with a poor prognosis. Recent reports suggest the prevalence of ILD to be 25 to 30 individuals per 100,000 population, and there is evidence to suggest that the incidence is increasing. This proposal is the major clinical project in this SCOR program. It is a collaborative effort that complements the work planned in other projects in the SCOR. This project will study patients with ILD with two histopathological patterns: granulomatous inflammation (berylliosis or sarcoidosis) and usual interstitial pneumonitis [(UIP), idiopathic pulmonary fibrosis (IPF) or progressive systemic sclerosis, (PSS-PF)]. The major objectives are: (1) to improve our understanding of the immunopathogenesis of pulmonary fibrosis, with special emphasis on those factors that appear to prevent the development of fibrosis and (2) to investigate the role of the antifibrogenic cytokine, interferon gamma (IFNgamma), in modulating the inflammatory and fibrotic process in ILD. Patients with granulomatous inflammation tend to have a more benign clinical course usually without progression to irreversible pulmonary fibrosis; conversely, those with conditions characterized by UIP tend to progress to fibrosis and eventually succumb to their illness. Consequently, preventing the fibrotic response appears to offer the best hope for reducing the impact of this problem on the health of individuals afflicted with ILD. We hypothesize that the prevention of pulmonary fibrosis is the result of two processes: first, antifibrotic factors produced by (or acting upon) the cells central to the process (lymphocytes, macrophages, mast cells, and fibroblasts); and second, rapid re-epithelialization of the injured lung. Both are required to successfully modulate the inflammatory response and inhibit the fibroblastic response thereby limiting the degree of fibrosis. The study design involves: (l) cross sectional studies to identify (in lung tissue and bronchoalveolar lavage) the presence or absence of anti- or pro- fibrogenic factors in the alveolar micro environment responsible for modulating the mesenchymal cell response; and (2) longitudinal studies to determine the ability of inhaled recombinant IFNgamma to modulate the fibroproliferative response. We expect these studies to yield valuable information about the cellular mechanisms involved in the transition from inflammation to wound healing, repair and fibrosis in the human lung. In addition, the study will allow us to further identify and characterize biomarkers that may be useful in the assessment of disease stage and in predicting disease progression and prognosis. Finally, these studies will improve our understanding of how to prevent or inhibit pulmonary fibrosis and thereby determine how to intervene in the disease process to treat or reduce the morbidity and mortality of this devastating illness.
Showing the most recent 10 out of 38 publications
