Abstract
The authors compared the effects of 6 weeks of dietary supplementation with either N-3 fatty acids (fish oil) or N-6 fatty acids (safflower oil) on the acute physiologic response to continuous endotoxin infusion in guinea pigs. Substantial evidence has accumulated to suggest that arachidonic acid metabolites may act as a common efferent signal in the pathogenesis of septic shock. Studies attempting to elucidate the physiologic effects of diets rich in N-3 fatty acids have centered on the altered formation and metabolism of prostanoids. Eicosapentaenoic acid (EPA) has been shown to be the metabolically active fatty acid in fish oil because of its structural similarity to the prostaglandin precursor, arachidonic acid (AA). Controlled dietary intake of selected fish oils rich in EPA and N-3 fatty acids have been shown to down-regulate eicosanoid metabolism leading to a more vasodilatory platelet and neutrophil antiaggregatory state compared with diets enriched with N-6 fatty acids. In previous studies, the authors have shown that dietary pretreatment with N-3 fatty acids attenuated the febrile response, reduced thromboxane formation to exogenous IL-1 administration, and improved survival after endotoxin challenge in guinea pigs. In the present study, it is hypothesized that diets enriched with N-3 fatty acids may alter the physiologic response to endotoxin, possibly by altering membrane phospholipids.
Three different experimental protocols were carried out after a 6-week feeding period in which animals received a standard diet containing either menhaden fish oil (N-3 fatty acids) or safflower oil (N-6 fatty acids). In the first experiment, animals were infused with endotoxin for 7 hours and blood pH, paCO2, bicarbonate, blood pressure, plasma lactate, serum phospholipid fatty acid profile, and histology (lung, liver, and kidney) were examined. In the second experiment, cardiac output and blood flow distribution during endotoxemia were determined. In the third experiment, the effect of either indomethacin or a specific thromboxane A2 receptor blocker (BM 13505) on the response to endotoxemia was examined. An additional subset of animals were infused with dichloroacetic acid (DCA), which prevents inhibition of the pyruvate dehydrogenase enzyme complex by endotoxin.
The mortality rate of animals infused with endotoxin alone was 20% in the safflower oil-fed group and 10% in the menhaden oil-fed group (not a statistically significant difference). No deaths were observed in animals pretreated with either indomethacin or BM 13505 regardless of diet. Safflower oil-fed animals developed an initial respiratory alkalosis followed by metabolic acidosis in response to endotoxin infusion, whereas fish-oil fed animals developed a mild respiratory alkalosis and no metabolic acidosis. Pre-treatment with indomethacin or BM 13505 had similar effects to N-3 fatty acid feeding in ameliorating the development of metabolic acidosis in safflower oil-fed animals, suggesting that prostaglandins and especially thromboxane, may be responsible for the development of some of the sequelae of endotoxemia. Safflower oil-fed animals had a sevenfold increase in lactate production compared with controls and a threefold increase compared with fish oil-fed animals. Infusion of indomethacin, significantly reduced the amount of lactate formed in safflower oil-fed animals given endotoxin, but had no additive effect in fish oil-fed animals. Administration of BM 13505 was only partially effective in reducing lactate levels, which remained significantly above control levels. The infusion of DCA failed to lower blood lactate levels in both groups given endotoxin. Safflower oil-fed animals developed a diffuse interstitial pneumonia with increased neutrophils and intravascular congestion. Fish oil-fed animals infused with endotoxin demonstrated intravascular congestion in their lungs without infiltrates. Examination of other tissues did not demonstrate any abnormalities in all groups, with the exception of the liver, which showed mild fatty infiltration in both dietary groups. Lung function was not severely compromised during the initial period of endotoxemia in either group. Endotoxin infusion caused a significant decrease in percent perfusion of both skin and muscle, regardless of dietary intake. However, in muscle, decreased perfusion was partly prevented by pre-treatment with N-3 fatty acids.
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