Idiopathic pulmonary fibrosis is a lethal, chronic lung disease with no effective therapy other than lung transplantation. The biochemical mechanisms involved in the pathogenesis of idiopathic pulmonary fibrosis are poorly characterized; however, reactive oxygen species are believed to be involved. Notably, the superoxide anion can activate collagenases as well as directly initiate collagen degradation. Collagen degradation products can stimulate inflammatory responses by neutrophils, resulting in further destruction of the extracellular matrix in the lung. If the inflammatory response is prolonged and/or severe the process may culminate in irreversible pulmonary fibrosis. The antioxidant enzyme extracellular superoxide dismutase (EC-SOD) is found in high concentrations in association with type I collagen in the lung. Thus, it is ideally situated to inhibit superoxide- mediated degradation of type I collagen. This proposal is designed to test the hypothesis that EC-SOD plays a central role in the pathogenesis of pulmonary fibrosis using both a mouse model and diseased human lungs. Transgenic mice that express elevated levels of EC-SOD, and knockout mice that do not express any EC-SOD will be utilized in a bleomycin model of pulmonary fibrosis. Experiments with these mice will allow us to directly determine the importance of EC-SOD in the pathogenesis of pulmonary fibrosis. To test our hypothesis that endogenous alterations in EC-SOD expression and/or biodistribution occur early in fibrotic injuries, de novo synthesis and proteolytic clearance of EC-SOD will be also be monitored in wild type animals treated with bleomycin. Studies will be conducted to delineate specific modifications of collagen in this model of pulmonary fibrosis, which we believe play a central role in the propagation of the injury. The effects of altered EC-SOD levels on this collagen damage will also be investigated to determine the role of EC-SOD in modulating collagen modification/degradation. Finally, immunochemical and biochemical analyses of EC-SOD activity and oxidatively modified collagen in human lungs with idiopathic pulmonary fibrosis will be performed to confirm and extend pathogenic mechanisms derived from the mouse model. When complete these studies will determine the importance of EC-SOD in pulmonary fibrosis. These studies are likely to elucidate novel biochemical mechanisms involved in pulmonary inflammation and fibrosis, and lead to the development of pharmacological agents that regulate these responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063700-02
Application #
6390549
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Musson, Robert
Project Start
2000-08-20
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$284,872
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Kliment, Corrine R; Oury, Tim D (2011) Extracellular superoxide dismutase protects cardiovascular syndecan-1 from oxidative shedding. Free Radic Biol Med 50:1075-80
Manni, Michelle L; Tomai, Lauren P; Norris, Callie A et al. (2011) Extracellular superoxide dismutase in macrophages augments bacterial killing by promoting phagocytosis. Am J Pathol 178:2752-9
Kliment, Corrine R; Englert, Judson M; Crum, Lauren P et al. (2011) A novel method for accurate collagen and biochemical assessment of pulmonary tissue utilizing one animal. Int J Clin Exp Pathol 4:349-55
Petersen, Steen V; Thogersen, Ida B; Valnickova, Zuzana et al. (2010) The concentration of extracellular superoxide dismutase in plasma is maintained by LRP-mediated endocytosis. Free Radic Biol Med 49:894-9
Ganguly, Koustav; Depner, Martin; Fattman, Cheryl et al. (2009) Superoxide dismutase 3, extracellular (SOD3) variants and lung function. Physiol Genomics 37:260-7
Kliment, Corrine R; Suliman, Hagir B; Tobolewski, Jacob M et al. (2009) Extracellular superoxide dismutase regulates cardiac function and fibrosis. J Mol Cell Cardiol 47:730-42
Kliment, Corrine R; Englert, Judson M; Gochuico, Bernadette R et al. (2009) Oxidative stress alters syndecan-1 distribution in lungs with pulmonary fibrosis. J Biol Chem 284:3537-45
Englert, Judson M; Hanford, Lana E; Kaminski, Naftali et al. (2008) A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis. Am J Pathol 172:583-91

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