ECSOD in Asbestos-induced Pulmonary Fibrosis

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DESCRIPTION (provided by applicant) Asbestosis is a debilitating disease caused by the inhalation of asbestos mineral fibers. Asbestosis is associated with chronic inflammatory reactions that can lead to the development of lung fibrosis years after the initial exposure. However, current treatment regimens are inadequate and new ones must be sought. It is well known that asbestos fibers generate reactive oxygen species in animal models of asbestosis, suggesting that oxidants play an important role in disease development. The enzyme extracellular supeoxide dismutase (ECSOD) is an antioxidant enzyme highly expressed in the lung and loss of ECSOD from the extracellular matrix (ECM) has been associated with pulmonary fibrosis in mice. ECSOD contains a heparin-binding domain that regulates its biodistribution in the ECM. This domain is sensitive to proteolysis, and removal of the heparin-binding domain may be an important mechanism regulating ECSOD levels in the ECM. ECSOD directly binds to type I collagen in alveolar septa, where it may protect collagen from superoxide-mediated fragmentation. Notably, collagen fragments are potent chemoattractants and activators of neutrophils. In addition, it has recently been shown that collagen fragments can induce apoptosis in a number of cell types. Therefore, any increase in superoxide production will accelerate both the inflammatory reactions and cellular destruction by initiating collagen degradation. The primary hypothesis to be tested in this proposal is that ECSOD protects against pulmonary fibrosis by preventing superoxide-mediated collagen degradation and apoptosis. To study this hypothesis, the applicant will pursue the following Specific Aims: 1) Investigate changes in ECSOD activity, biodistribution and sites of synthesis in mouse lungs at different stages of asbestos-induced lung injury, 2) Assess the structural effects of asbestos deposition on type I collagen, and 3) Determine the stimulus for and extent of programmed cell death in lungs of asbestos-treated mice.