(Adapted from the applicant's abstract and Specific Aims.) This is a renewal application to evaluate the role of antioxidant enzymes in modulating lung airway and vascular diseases. A finding from the original funding period was that the extracellular form of superoxide dismutase (EC- SOD) is a protein uniquely highly expressed in the lung. It was found to be primarily localized in the extracellular spaces surrounding smooth muscle cells in airways and in the pulmonary vasculature. The hypothesis to be tested is that EC-SOD plays a critical role in regulating the activity of nitric oxide (NO) in the lung. The possible mechanisms for EC-SOD regulation of NO activity include: 1) scavenging O2- and thereby preventing the reaction of O2- with NO, or 2) catalyzing the reversible conversion between NO and the nitroxyl anion (NO-). The distributions and physical relationships of nitric oxide synthase (the enzymatic source of NO) and EC-SOD in pulmonary airways and in the pulmonary vasculature will be determined. Both in vitro and in vivo animal models will be used to demonstrate the role of EC-SOD in regulating airway and vascular tone in the lung. The Specific Aims are to: 1) create tools for the study of EC-SOD in an animal model that will allow the biological function of EC-SOD to be explored; 2) immunolocalize EC-SOD in airways and pulmonary vasculature; 3) immunolocalize nitric oxide synthase in airways and pulmonary vasculature; 4) study the mechanisms of airway bronchomotor tone regulation; 5) study the mechanisms of pulmonary vasculature tone regulation; and 6) screen human patients for gene defects in EC-SOD. The proposed studies may demonstrate that EC-SOD plays a critical role in regulating both pulmonary airway and vascular tone. Gene defects for this protein could play a critical role in common diseases such as asthma and pulmonary vascular hypertension. By demonstrating the physiologic importance of this enzyme and characterizing gene defects related to it, new pharmacologic therapies may be identified for the treatment of diseases involving both airway hyperreactivity and pulmonary vascular hyperreactivity.

R01HL042609

1989-05-01

1998-04-30