Evans, David Andrew; (1990) Tumour necrosis factor as a mediator of endotoxaemia. Doctoral thesis (M.D), UCL (University College London).

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Abstract

The effects of endotoxaemia are thought to be mediated by endogenous host substances. It has been suggested that the recently isolated cytokine, Tumour Necrosis Factor (TNF), is such a substance. To examine this possibility the effects of TNF were studied in the dog and the findings were compared with known effects of endotoxin. Secondly, to assess the dependence of TNF effects upon endogenous prostaglandin synthesis, TNF was given after administration of the cyclooxygenase inhibitor, Ibuprofen. Further studies questioned whether or not some TNF effects might be due to an increased absorption of endotoxin from the gut. In anaesthetised dogs an infusion of TNF caused falls In systemic, pulmonary, central venous and pulmonary capillary wedge pressures. There was a four fold increase In urine volume and significant pyrexia, tachycardia, hyperventilation and hypermetabolism. In addition, leucopenia and increased circulating concentrations of stress hormones, lactate and pyruvate were observed. Peripheral glucose uptake increased and though glucose production also rose this was insufficient to meet demands. In consequence, blood glucose fell. Urinary nitrogen excretion was increased but this extra nitrogen was not drawn from the periphery, suggesting a visceral source. These alterations occured in the absence of severe hypotension or acidosis. Many of the changes were reproduced in two conscious animals. Pretreatment of anaesthetised animals with Ibuprofen abolished haemodynamic changes whilst attenuating some of the other responses. Studies of TNF administration after removal of the bowel suggest that several TNF effects do not depend upon an increased absorption of gut endotoxin; for many parameters however no firm conclusions could be drawn from the data. These findings support the hypotheses that TNF Is a mediator of endotoxaemia and that some of Its effects are mediated by prostaglandins.

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