Project 1, Mechanisms of Injury and Inflammation in Fibrotic Lung Disease, will focus on human studies of the lung in transition from injury to fibrosis. A central hypotheses proposes that injury precedes fibrosis, and inflammation without injury resolves without scarring. The alveolar macrophage will be examined as a key amplifier cell which augments injury by recruiting neutrophils, inflammation by stimulating lymphocytes, and fibrosis by enhancing fibroblast proliferation. Diseases which ultimately proceed to fibrosis should evidence early injury, while inflammation which resolves without fibrosis should not show evidence of injury. We will utilize bronchoalveolar lavage (BAL) to assess specific markers of injury, inflammation, and fibrosis. In BAL, surfactant lipids, protein, and angiotensin converting enzyme will mark epithelial, alveolar-capillary membrane, and endothelial injury respectively. Inflammation will be reflected by BAL leukocytes, and collagen synthesis by N-terminal procollagen peptides. Idiopathic pulmonary fibrosis and adult respiratory distress syndrome (ARDS) will represent diseases in which fibrosis is the almost universal outcome. Hypersensitivity pneumonitis will be used as a contrasting chronic immune-inflammatory interstitial disease in which fibrosis is uncommon. Normal volunteers will be compared with these patient groups. Alveolar macrophage secretion of neutrophil chemotactic activity will be measured, and the augmenting effects of oxygen explored. Interleukin-1 secretion by BAL macrophages will be compared among the groups as a potentially important mechanism of lymphocyte recruitment. Macrophage derived growth factor (MDGF) will be measured through the activities of Project 11. These inter-related efforts will provide for a more complete understanding of the mechanisms which induce and govern diffuse interstitial lung diseases.
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