Manni, Michelle Lynn
(2011)
LEUKOCYTE-DERIVED EXTRACELLULAR SUPEROXIDE DISMUTASE IN PULMONARY DISEASE.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The antioxidant enzyme extracellular superoxide dismutase (EC-SOD) is abundant in the lung and limits inflammation and tissue injury in response to many pulmonary insults. Previous studies reported a loss of full-length EC-SOD from the lung parenchyma with accumulation of proteolyzed EC-SOD in the airspace after interstitial lung injury. However, following airspace only inflammation (pneumonia), EC-SOD accumulates in the airspace without a loss from the interstitium, suggesting this antioxidant may be released from an extrapulmonary source.Because leukocytes are known to express EC-SOD and are prevalent in the bronchoalveolarlavage fluid after injury, it was hypothesized that these cells may transport and release EC-SODinto airspaces. To investigate this, bone marrow chimeras were generated using wild-type andEC-SOD knockout (KO) mice. Following intratracheal treatment with asbestos, reconstituted mice without pulmonary EC-SOD expression, but with EC-SOD in infiltrating and resident leukocytes did not have detectable levels of EC-SOD in the airspaces. In addition, leukocytederived EC-SOD did not significantly lessen inflammation or early stage fibrosis.Although these results indicate that leukocyte-derived EC-SOD is not influential in asbestos-induced interstitial lung injury, EC-SOD in these cells may play a role in attenuating pneumonias and other inflammatory diseases. To test this hypothesis, wild-type and EC-SOD KO mice were given Escherichia coli pneumonia. Notably, even though EC-SOD KO mice had greater pulmonary inflammation than wild-type mice, there was less bacterial clearance from their lungs following infection. While EC-SOD expression has been previously reported in macrophages and neutrophils, its function and subcellular localization in these inflammatory cells is unclear. In this study, EC-SOD was found to be in membrane bound vesicles of phagocytes. This finding led to the hypothesis that inflammatory cell EC-SOD may play a role in antibacterial defense. To investigate this, phagocytes from wild-type and EC-SOD KO mice were evaluated. While macrophages lacking EC-SOD produced more oxidants than EC-SOD expressing cells after stimulation, they had significantly impaired phagocytosis and bacterial killing ability. Overall, these studies suggest that while EC-SOD inside leukocytes does not contribute to interstitial lung injuries, it plays a central role in mediating bacterial infections by facilitating bacterial clearance and limiting inflammation by promoting phagocytosis.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Manni, Michelle Lynn | mlm45@pitt.edu | MLM45 | |
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| ETD Committee: |
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| Date: |
28 February 2011 |
| Date Type: |
Completion |
| Defense Date: |
10 January 2011 |
| Approval Date: |
28 February 2011 |
| Submission Date: |
28 February 2011 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| 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: |
antioxidant; extracellular superoxide dismutase; host defense; inflammation; innate immunity; lung |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-02282011-105626/, etd-02282011-105626 |
| Date Deposited: |
10 Nov 2011 19:31 |
| Last Modified: |
15 Nov 2016 13:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/6421 |
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