The metabolic effects of endotoxin and tumour necrosis factor in the Wistar rat

Bibby, David Charles (1989) The metabolic effects of endotoxin and tumour necrosis factor in the Wistar rat. University of Southampton, Doctoral Thesis.

Abstract

Endotoxin is a potent stimulator of the acute phase responses to infection and many of its actions are thought to be mediated via the release of tumour necrosis factor and interleukin-1 from mononuclear phagocytes. Data in this thesis reveals that endotoxin can induce hypozincaemia, hypoalbuminaemia, changes in body temperature, an increase in serum urea concentration, a rise in liver zinc and protein content and an increase in spleen protein in the Wistar rat. These reponses are variably affected by factors such as ambient temperature, urethane anaesthesia, type of endotoxin, route of endotoxin administration and pregnancy. Tumour necrosis factor (TNF) is shown to mimic many of the responses previously ascribed to endotoxin, including: fever at low doses; hypothermia at high doses; hypozincaemia; hypoalbuminaemia; hypercupraemia; increases in liver zinc and metallothionein content; liver protein gain and tibialis protein loss. The involvement of the eicosanoids in the TNF-induced responses was investigated using a 5-lipoxygenase inhibitor (AA861) and a cyclo-oxygenase inhibitor (indomethacin). The hypothermia and hyperkalaemia produced by TNF are both prostaglandin- and leukotriene-dependent whereas the TNF-stimulated hypoalbuminaemia is leukotriene-dependent. Changes in zinc metabolism evoked by TNF are eicosanoid-independent. An increase in the hypothalamic level of prostaglandin E₂ (PGE₂) is the proposed mechanism by which pyrogens produce a fever. In this thesis endotoxin and TNF are both shown to stimulate PGE₂ synthesis by minced rat hypothalami. Aged rats are demonstrated to have a reduced febrile response to TNF which is associated with a reduced capacity of their hypothalami to generate PGE₂, when challenged with TNF or endotoxin, in vitro. Minced rat hypothalami can not produce leukotriene C₄ (LTC₄) when incubated with endotoxin or TNF, suggesting that a direct stimulation of hypothalamic LTC₄ synthesis is not the mechanism by which TNF elicits hypothermia, although this response is leukotriene-dependent. Feeding a coconut oil-enriched diet is shown to affect the body temperature changes induced by endotoxin and TNF and the TNF-stimulated changes in liver protein content, tibialis protein content, serum copper and albumin concentrations and liver and spleen zinc contents. The ability of minced hypothalami to generate PGE₂, when stimulated with TNF or endotoxin in vitro, is attentuated in rats pre-fed on the coconut oil-enriched diet. Insufficient eicosanoid production may therefore underlie the inhibition of TNF- and endotoxin-induced responses caused by this diet. Whether this is due to its low concentration of the eicosanoid precursor, linoleic acid, or a possible alteration in receptor activity is discussed.

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