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Title: The role of base excision repair in regulating endotoxin induced inflammation
Author: Carter, Alan Neil
ISNI:       0000 0004 2737 3878
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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Endotoxins a component of the outer membrane of the cell wall of gram negative bacteria, stimulate the innate immune system to elicit an inflammatory response in mammals. Deletion of base excision repair (BER) genes has been reported to decrease the immune response to endotoxin in mouse models. It is currently unknown whether this role is limited to a few select proteins or a result of the general function of the BER pathway. The aim of this study was to identify if the loss of other BER proteins would trigger a similar response by measuring the levels of inflammatory cytokines produced and certain biomarkers of oxidative stress. To facilitate this, a new strain of NEIL1-/- mice was successfully created as well as a putative NEIL2-/- strain. A previous strain of NEIL1-/- mice displayed a sporadic obese phenotype, our NEIL1-/- mice showed no significant increase in bodyweight when compared to WT mice. Whilst there were significant differences in the serum content of cytokines IL-6, IL-12, IL-10 and IL-4 between wildtype, NEIL1-/- and OGG1-/- mice challenged with lipopolysaccharide (LPS, the active component of endotoxin). When compared to wildtype animals both NEIL1-/- and OGG1-/- mice produced lower levels of the Th1 cytokine IL-6 (♂ 1 h; p<0.05 and ♀ 24 h; p<0.01), and the Th2 IL-10 cytokine (♀ 6 and 24 h; p<0.01) along with other sex and genotype specific differences. When comparing LPS induced organ damage in NEIL1-/- and wildtype mice there were no significant differences in myeloperoxidase (MPO) activity or malondialdehyde (MDA) concentration due to genotype. However, there were significant differences observed in glutathione (GSH) levels in the heart (p=0.01), lung (p=0.05), liver (p=0.05) and ileum (p=0.05) that when considered alongside a significant increase in the weights of adrenal glands in NEIL1-/- knockout (♂ p=0.05, ♀ p=0.03) mice were suggestive of a raised level of adrenaline. The OGG1-/- mice displayed no significant genotype x treatment interaction in MPO activity, MDA levels or GSH levels. However, genotype x sex interactions were observed in the liver and lung tissues of OGG1-/- for MPO (lung p<0.01, liver p=0.02), MDA (lung p<0.01) and GSH (lung p=0.05, liver p=0.04) indicating that female OGG1-/- mice had greater protection from the oxidative effects of LPS induced inflammation. In conclusion whilst the knockout of OGG1 and NEIL1 genes had an effect on the inflammatory signalling response, this effect was not great enough to impact upon oxidative stress markers of inflammation within the tissues sampled. The mechanism of how this is accomplished is at present unclear and worthy of further study.
Supervisor: Povey, Andrew; Elder, Rhoderick Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available