The effect of E. coli endotoxin on the metabolic responses of Wistar rats

Abstract

Escherichia coli endotoxin is a potent stimulator of IL-1 and cachectin/TNF production from macrophages. Both IL-1 and cachectin/TNF have been implicated in muscle protein loss, acute phase protein synthesis, fever, depressed serum zinc, and elevate serum corticosterone concentration. 

The source of mobilized amino acids during infection and inflammation is believed to come from muscle proteolysis. Data presented in this thesis clearly indicated that the relative contribution to the negative N balance by skin and bone should not be neglected. The reduction in fractional rates of protein synthesis measured by injection of flooding doses of [³H]-phenylalanine in the endotoxin was in the order of skin (abdomen) > bone > muscle. These also run parallel with the reduction of protein content. Total liver protein synthesised per day in the endotoxin-treated animals was increased. 

Some preparations of E. coli endotoxin (phenol and TCA extract) (ED) are hypothermic and enhanced greater reduction in food intake and body weight loss; while the butanol extracts of endotoxin (ES) caused fever, produced less anorexia and body weight loss. The reason for these differences is not clear but may be due to the production of potent shock mediator, cachectin/TNF and/or stimulation on the sympatho-adrenal nervous sytem. The latter action may be modulated by protaglandins since indomethacin prevented ED-induced hypothermia. 

Administration of the β-adrengeric blocker propranolol, blunted the ES-induced hyperthermia and delayed the recovery of ED-induced hypothermia. The contribution of heat from non-thermogenesis in brown adipose tissue is unimportant in the production of fever since the binding of [^3H]-GDP to BAT mitochondria in both hyperthermic and hypothermic animals did not differ from that of the saline-treated animals. 

The present investigation suggests the existence of the diurnal variation in the body temperature responses to endotoxin. Both ES and ED produced hypothermia. Furthermore, reversed the lighting cycles (6pm-6am) (RL) affected : serum zinc, corticosterone, except for tissue protein loss. Both ES and ED produced hypothermia in the RL-adopted rats. 

The production and actions of IL-1 and cachectin/TNF may be affected by dietary fatty acids concentration and composition. Feeding rats with diets either enriched with or supplemented by 30g/kg, 90g/kg and 200g/kg of hydrogenated coconut oil (HCO); or by the 9og/Kg fish oil (FO) abolished most of the metabolic responses to ED injection. Both HCO and FO could influence the response via a reduction in prostaglandins and leukotrienes by reducing the formation of arachidonic acid (AA) precursor of eicosanoids. Fatty acids composition analysis from the PC fraction of the spleen showed a decreased amount of AA in the order of FO > HCO > CO. 

Pretreatment with the cycloxygenase inhibitor, indomethacin blocked body weight loss, prevented protein loss from peripheral tissues, and affected the elevation of serum corticosterone; whereas the lipoxygenase inhibitor AA861 inhibited ED-induced hypozincemia, and muscle cathepsin B activity. Total liver protein was unaffected by inhibitors, and HCO or FO feeding. T ese data suggested that many of the endotoxin-induced metabolic changes are controlled by metabolites of AA, and that the acute-phase proteins synthesis by the liver is independent of eicosanoids production. Dietary fats manipulation moderated the metabolic responses to E. coli endotoxin through both pathways. (D74421/87)

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