Oxidative stress and tissue remodeling are involved in the development of fibrosis of the lung and heart. Extracellular superoxide dismutase (EC-SOD) is an important antioxidant enzyme that has been shown to limit inflammation and fibrosis. Idiopathic pulmonary fibrosis is a lung disease characterized by severe, progressive interstitial fibrosis. Cardiac fibrosis has various causes but is a fatal side effect of treatment with the chemotherapeutic doxorubicin. Both of these diseases involve oxidant/antioxidant imbalances and can be studied through animal models. It was hypothesized that one mechanism through which EC-SOD protects the lungs and heart from inflammation and fibrosis is by preventing oxidative shedding of extracellular matrix components, specifically syndecans.
In the lung, wild type and EC-SOD KO mice were treated with titanium dioxide, asbestos, or Bleomycin. Over the course of injury, EC-SOD KO mice have significantly higher levels of shed syndecan-1 and -4 in their bronchoalveolar lavage fluid and tissue. By IHC staining, the lung distribution of EC-SOD decreases in areas of fibrosis while syndecan-1 increases. Furthermore, in vitro, EC-SOD prevents syndecan-1 shedding from epithelial cells through its antioxidant activity and by directly binding to syndecan-1. Shed syndecan-1 is chemotactic to neutrophils and inhibits wound healing. In the heart, the signifiance of EC-SOD on normal heart morphology, fibrosis, and cardiac function were evaluated in wild type and EC-SOD KO mice in a doxorubicin-induced LV fibrosis model. The lack of EC-SOD causes LV posterior wall thinning and ventricular dilation without an insult. After an oxidative insult induced by doxorubicin, EC-SOD KO mice lost significantly more cardiac function compared to wild-type mice, had enhanced inflammatory cell recruitment, increased shedding of syndecan-1 from the heart and increased caspase-3 activation or apoptosis.
In summary, this study shows that EC-SOD is important in the maintenance of normal cardiac morphology, the development of cardiac fibrosis, inflammation, apoptosis, and the loss of function associated with oxidative cardiac injury. In the lung, this investigation shows that the loss of pulmonary EC-SOD leaves syndecan-1 vulnerable to oxidative stress and that oxidant-induced loss of cell surface syndecan-1 impairs re-epithelialization, induces inflammation, and promotes a fibrotic microenvironment in the lung.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-06042009-072833 |
| Date | 09 June 2009 |
| Creators | Kliment, Corrine RaShelle |
| Contributors | Charleen T. Chu, MD, PhD, Bruce A. Freeman, PhD, Wendy M. Mars, PhD, Tim D. Oury, MD, PhD, Cary Wu, PhD, Steven D. Shapiro, MD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-06042009-072833/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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