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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-10022005-153926 |
| Date | 20 October 2005 |
| Creators | Tan, Roderick Jason |
| Contributors | Tim D. Oury, Cary Wu, Prabir Ray, Wendy M. Mars, Charleen T. Chu |
| 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-10022005-153926/ |
| 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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