Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491315
Title: Surfactant protein D in infection and inflammation in the lung : the therapeutic potential of a recombinant fragment of SP-D.
Author: Mackay, Rose-Marie
Awarding Body: Oxford Brookes University
Current Institution: Oxford Brookes University
Date of Award: 2007
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Abstract:
This thesis examines the roles played by the lung collectins, surfactant proteins A and 0, and their role in innate immunity in the lung. Since the generation of mice deficient in the lung collectins the important role of these proteins in both lung defence and homeostasis has become evident. SP-A -f- mice are more susceptible to infection and SP-D -f- mice have quite a distinct phenotype, which is comparable to human emphysema with a chronic low-grade inflammation. The first three results chapters of this thesis examine the interactions of the lung collectins with bacteria and how these interactions in vitro may affect the pathogenicity in vivo. In vitro investigations into Haemophilus illfluellzae with mutated LPS structures conversely uncovered the interactions of SP-D was through the core regions of LPS rather than the core-terminal oligosaccharides described in previous studies. A murine model of H. illfluenza infection was set up to compare H. influellza wild-type to the mutant strains with regards to the infectivity. As predicted from the in vitro investigations the mutant strains of H. influenza were shown to be less pathogenic than the wild-type bacteria. Fusobacterium .1lllcleatum has been associated with premature birth in humans and murine models of F.llucleatetm infection, the lung collectins are also expressed in the amniotic epithelium and chorionic membrane as well as the amniotic fluid during pregnancy. Native human SP-D, SP-A and rfhSP-D were all shown to bind and interact with F.llucleatum. ill vitro Both forms of SP-D had the ability to inhibit the growth of the pathogen and modulate the cytokine responses to infection in RAW cells. The next chapter is an investigation into the effects of administering a recombinant fragment of SP-D into SP-D-f-mice. The replacement of SP-D using rfhSP-D corrected the inflammation and excess lipid accumulation in the lung with a decrease in apoptotic cell number and a partial resolution of inflammation. Finally, bone marrow transplantations were performed to investigate the mechanisms of SP-D production. The transplant resulted in SP-D expression in the lung shown by RT-PCR. The re-expression of SP-D attenuated many of the abnormaliti~s associated with SP-D deficiency, such as increasing alveolar numbers, and corrected the alveolar proteinosis. However, the cellular inflammatory processes could not be corrected by the transplant. Thus the ability of SP-D-I- mice to express SP-D after being transplanted with bone marrow from wild-type mice resulted in phenotypic changes compared to the SP-D-I- controls. Similarly, wild-type mice showed slight lung abnormalities usually associated with SP-D deficiency, after being transplanted with SP-D-Ibone marrow. The clinical implications of these findings arc discussed in the introduction to this thesis, with focus on the therapeutic potential of the recombinant fragment of SP-D in patients who express low levels of these proteins. This includes such conditions as cystic fibrosis, adult emphysema and in chronic neonatal lung diseases.
Supervisor: Not available Sponsor: Not available
Qualification Name: Oxford Books University, 2007 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.491315  DOI: Not available
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