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Title: Effects of fatty acids on inflammatory markers studied in vivo and in vitro
Author: Mohd Yusof, Hayati
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2008
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Inflammation involves interactions amongst many different cell types as a defense mechanism of the body. Inflammation is also involved in cardiovascular disease (CVD). The role of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) in modulating the inflammatory response has been proposed. The aim of these studies is to investigate the effects of modest intakes of n-3 PUFAs on CVD risk factors especially inflammatory markers, including soluble adhesion molecules, in adult humans with and without CVD and to identify the effects of selected fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on inflammatory responses, especially adhesion molecule expression in cultured human endothelial cells of different origin (fetal vs. adults; vein vs. artery). In the first in vivo study, healthy middle-aged men aged 35-60 years were randomized to 1.8 g/d EPA plus 0.23 g/d DHA (n = 9) or placebo oil (2.6 g/day medium-chain saturated fatty acids; n = 11) for 8 weeks. In a second in vivo study, patients awaiting carotid endarterectomy were randomised to 0.8 g/d EPA plus 0.67 g/d DHA (Omacor; n = 47) or olive oil (n = 53) as placebo for between 7 and 102 days until surgery. Supplementation with fish oil in healthy men resulted in a 363% increase in EPA and only a 13% increase in DHA in plasma phosphatidylcholine (PC). On the other hand, Omacor supplementation resulted in significantly increased EPA and DHA in plasma PC by 161% and 70%, respectively. In healthy subjects, there was very little effect of n-3 fatty acids on the risk factors measured (lipid profiles and inflammatory markers), apart from a reduction in plasma soluble intercellular molecule-1 (sICAM-1) concentration compared with placebo (P = 0.05). The change in plasma sICAM-1 concentration was significantly inversely associated with the change in DHA in plasma PC (r = -0.675; P = 0.001). Supplementation with Omacor, however, significantly decreased total plasma cholesterol, triacylglycerol (TAG) and LDL-cholesterol concentrations (P < 0.001) by 13%, 14%, and 5% respectively. In terms of inflammatory markers, supplementation with Omacor significantly decreased sE-selectin by 23% (P = 0.006) and sVCAM-1 by 25% (P < 0.0001), and had no significant effects on other plasma inflammatory markers including sICAM-1 even though trends toward decreases in these markers were observed. This study suggests some anti-inflammatory actions of moderate dose of Omacor in carotid endarterectomy patients. Based on correlation analysis between mRNA expression of inflammatory markers in plaque and plasma concentrations, it seems that soluble inflammatory markers cannot be used to reflect the expression of these molecules at the cell surface, i.e. in the vasculature or in the plaque. In the in vitro experiments the inflammatory stimulus lipopolysaccharide (LPS) up-regulated all three adhesion molecules studied at the protein (as assessed by ELISA) and the mRNA (as assessed by reverse transcription and real-time PCR) levels. VCAM-1 was affected by fatty acids to a greater extent than ICAM-1 or E-selectin. Amongst the fatty acids, DHA has the greatest and the most consistent effects on adhesion molecule protein expression. EPA was also a potent fatty acid inhibitor of adhesion molecule expression at the mRNA level. Some effects of stearic, oleic and arachidonic acids on adhesion molecules were also seen. The effects of fatty acids on the adhesion molecule expression were fatty acid, adhesion molecule and endothelial cell specific. The inhibitory effects of fatty acids were more pronounced in vein endothelial cells than arterial endothelial cells. The precise underlying mechanism on how fatty acids affect adhesion molecule expression remains to be clarified.
Supervisor: Calder, Philip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RB Pathology ; QR180 Immunology