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Extracellular Superoxide Dismutase and Matrix Metalloproteinases in Pulmonary Fibrosis

Tan, Roderick Jason (2005) Extracellular Superoxide Dismutase and Matrix Metalloproteinases in Pulmonary Fibrosis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Pulmonary fibrosis is the collective name for disorders characterized by excessive deposition of interstitial collagen in the lung. Although the molecular mechanisms underlying pulmonary fibrosis are poorly understood, current evidence implicates both oxidant/antioxidant and protease/antiprotease imbalances in disease development. Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme protective against the development of pulmonary fibrosis in experimental models. EC-SOD localization in the lung is regulated by a heparin-binding domain conferring affinity for the extracellular matrix. This domain is susceptible to proteolytic removal, allowing EC-SOD to diffuse from the matrix. While the in vivo protease of EC-SOD has not been identified, it is known that members of the matrix metalloproteinase (MMP) family of proteases are upregulated in pulmonary fibrosis and could contribute to EC-SOD diffusion from the matrix. Furthermore, latent MMPs can be activated by oxidants, indicating that loss of EC-SOD from the matrix could lead to increased MMP activity. It was hypothesized that the depletion of EC-SOD from the lung and interrelated increase in MMP activity contribute to pulmonary fibrosis development. To examine this hypothesis, a mouse model of pulmonary fibrosis initiated by asbestos fibers (asbestosis) was developed. This injury caused depletion of EC-SOD from the lung parenchyma. Simultaneously, EC-SOD accumulated in the airspaces entirely due to release from airspace inflammatory cells. Depletion from lung matrices may be important since EC-SOD knockout mice develop worse inflammation and fibrosis after asbestos exposure. The metalloproteinases, MMP-2 and MMP-9, were upregulated after asbestos exposure. MMPs appeared to be important in asbestosis development, as global pharmacologic inhibition of MMPs decreased disease severity. MMP inhibition also reduced airspace EC-SOD accumulation, indicating a role for MMPs in EC-SOD localization. EC-SOD knockout mice treated with asbestos did not have significantly different MMP-2 and -9 activity compared to wild type mice. However, in bleomycin injury, knockout mice had increased airspace MMP-9, indicating a role for EC-SOD in the regulation of this protease. In summary, our data provides strong evidence for contributory roles for both EC-SOD and MMPs in the development of pulmonary fibrosis and additionally provides novel insights into EC-SOD regulation in the lung.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Tan, Roderick Jasonrjtst19@pitt.eduRJTST19
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairChu, Charleen Tctc4@pitt.eduCTC4
Committee CoChairOury, Tim Dtdoury@pitt.eduTDOURY
Committee MemberWu, Carycarywu@pitt.eduCARYWU
Committee MemberRay, Prabirrayp@pitt.eduRAYP
Committee MemberMars, Wendy Mwmars@pitt.eduWMARS
Date: 20 October 2005
Date Type: Completion
Defense Date: 6 September 2005
Approval Date: 20 October 2005
Submission Date: 2 October 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: asbestos; asbestosis; inflammation; lung; oxidative stress; protease; pulmonary fibrosis
Other ID:, etd-10022005-153926
Date Deposited: 10 Nov 2011 20:02
Last Modified: 15 Nov 2016 13:50


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