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Manni, Michelle Lynn (2011) LEUKOCYTE-DERIVED EXTRACELLULAR SUPEROXIDE DISMUTASE IN PULMONARY DISEASE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Manni, Michelle Lynnmlm45@pitt.eduMLM45
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPiganelli, Jon D.jdp51@pitt.eduJDP51
Committee MemberFreeman, Bruce A.freerad@pitt.eduFREERAD
Committee MemberFeghali-Bostwick, Carol A.feghali2@pitt.eduFEGHALI2
Committee MemberChu, Charleen T.ctc4@pitt.eduCTC4
Committee MemberOury, Tim D.tdoury@pitt.eduTDOURY
Committee MemberMars, Wendy M.wmars@pitt.eduWMARS
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:, etd-02282011-105626
Date Deposited: 10 Nov 2011 19:31
Last Modified: 15 Nov 2016 13:36


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