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Modulation of inflammatory responses by mitochondrial targeted antioxidants

Sepsis is a life threatening progression of a trauma or pathogen initiated systemic inflammatory response. Current treatment is supportive and depends mainly on antibiotics, fluids, and the careful administration of oxygen therapy. As sepsis progresses, it becomes a dysregulated inflammatory response, characterised by oxidative stress and excessive production of inflammatory cytokines, mitochondrial dysfunction and loss of antioxidant protection. Previous work on cells and animals has shown that novel antioxidants targeted to mitochondria may have a beneficial effect. To induce an inflammatory response and mitochondrial dysfunction, a human umbilical vein endothelial cell (HUVEC) in vitro mixed sepsis model with 0.2 μg/ml lipopolysaccharide (LPS) plus 20 μg/ml peptidoglycan (PepG) was used in the presence of a mitochondrially targeted vitamin E derivative, MitoVit E, and compared to the non-targeted vitamin E forms, Trolox and DL α-tocopherol acetate. Gene expression analysis was performed by quantitative polymerase chain reaction (qPCR) of the Toll-like receptor (TLR) 2 and 4 pathways from cells treated with the antioxidant +/- LPS/PepG for 4 h. Results showed that MitoVit E differentially regulated 11 genes compared to just four genes for the non-targeted forms of vitamin E. MitoVit E, Trolox and vitamin E were able to blunt IL-6 and IL-8 cytokine response in a dose-dependent manner. Inhibition of NFĸB gene and accessory protein expression was different for each antioxidant investigated along with effects on other inflammatory signalling proteins STAT 3 and MyD88. In addition, the antioxidants regulated radical production to similar extents, but had different effects on the reduced glutathione/oxidised glutathione, mitochondrial metabolic activity, mitochondrial membrane potential, oxygen consumption and mitochondrial number. In conclusion, MitoVit E showed encouraging effects in preventing dysregulation of the inflammatory response, maintaining mitochondrial membrane potential and radical production and normal cell function.
Date January 2014
CreatorsMinter, Beverley E.
PublisherUniversity of Aberdeen
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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