Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized pathologically by a chronic inflammatory process (""""""""alveolitis"""""""") that precedes and likely controls the alterations in connective tissue matrix that eventually destroys the normal lung architecture. The mechanisms involved in this process are not known. A complex cell-cell interactive sequence, involving principally neutrophils, lymphocytes, macrophages, fibroblast, and epithelial cells is believed to be responsible. This proposal is designed to study patients with IPF and patients with progressive systemic sclerosis (PSS), with and without associated lung disease, in two ways: a) in a cross-sectional comparison, examining for each of our experimental parameters (bronchoalveolar lavage, high resolution, thin-section computer tomography, neutrophil or monocyte labeled scintigraphy); and b) in a serial, longitudinal evaluation while monitoring the progression of disease. The study of PSS patients, without disease or with subclinical disease, are particularly useful because they will allow examination of the early events in the pathogenesis of IPF. The long-term goal of this project is to determine what alterations in cellular composition, function and trafficking occurs in the lung parenchyma of patients with IPF and to relate these alterations to the disease stage, prognosis, and therapeutic responsiveness. The major objectives of our study are: (1) to continue our prospective, longitudinal study of carefully defined cases of IPF; (2) to initiate a study of patients with PSS, a disease that provides a useful paradigm for studying the early events of the disease; (3) to determine the role of the lymphocyte in IPF, by defining the subset of T lymphocytes that are responsible for modulating macrophage function; (4) to establish the role of non-invasive techniques (BAL, HRCT scanning and scintigraphy -- neutrophil and monocyte labelled cells) in assessing the activity of inflammation in carefully evaluated patients; (5) to determine the relationship of these results to the -- carefully defined and serially obtained -- clinical, radiographical, and physiological findings and to the histopathologic abnormalities (in patients that undergo lung biopsy, predominantly IPF cases). (6) to perform studies utilizing blood, BAL fluid and lung tissue in an effort to understand the pathogenic mechanisms that underlie the inflammatory/immune cellular injury and fibrosis that characterizes this disease (N.B. Each of these sampling sites is important since they provide their own information that is frequently different from, yet complementary to, the others). We expect that these analyses will determine the role of these techniques in: identifying the stages and activity of the disease process and predicting the clinical course and response to therapy.
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