Endotoxins or lipopolysaccharides (LPS), highly toxic component of the outer membrane of gram-negative bacteria, are normally present in the mammalian gut lumen.In this thesis, I investigated, in laboratory animals, whether these gut-derived endotoxins play a role in pathophysiology resulting from intestinal dysfunctions caused by intestinal ischaemia and heat-stress.In primates, reperfusion of the splanchnic region after a temporary ischaemia was followed by a rapid increase in LPS concentration, first in the hepatic portal plasma and, ten minutes later, in the systemic arterial plasma. Rises in plasma LPS concentrations during or following the temporary intestinal ischaemia was prevented by prophylactic administrations of corticosteroids, anti-LPS IgG antibodies and oral, non-absorpable, antibiotics agents which appear to stabilize cellular membranes, aid the reticuloendothelial system in removal of LPS from the circulation and destroy the intestinal aerobic gramnegative bacteria respectively. In addition, administration of therapeutic anti-LPS antibodies also rapidly reduced the plasma LPS concentrations to baseline during an endotoxaemia. In a control heat-stress model, elevations in plasma LPS concentration commenced at rectal temperatures greater than 41,SoC. Like the intestinal ischaemia model, this occurred first in the hepatic portal plasma, and 10-15 minutes later, in the systemic arterial plasma. Peak plasma LPS levels of about 0,3 ng/ml, measured in heat-stressed primates, have proved in previous studies, to be toxic. A rapid decline in mean arterial pressure was followed by increases in plasma LPS concentrations and heart rates. Reductions in splanchnic blood flow and consequent local ischaemia coupled with thermal injury to the intestinal wall and the liver, may have permitted rises in plasma LPS concentration. Furthermore, as in the ischaemia model, prophylactic administrations of corticosteroids, anti-LPS IgG antibodies, and oral, nonabsorbable antibiotics prevented a rise in plasma LPS concentration. Of importance, prophylaxis with intravenous corticosteroids and 'anti-LPS IgG antibodies increased the survival rates significantly in heat stroke in primates. In addition, monkeys having high titres of "natural" antiLPS IgG antibodies had lower plasma LPS concentrations and survived the induced-heat stroke. It is suggested that other pathophysiologic conditions which compromise the integrity of the gut wall would also lead to the development of an endotoxaemia, and that gutderived endotoxins contribute to the athogenesis of heat stroke and treatments with corticosteroids and anti-LPS IgG antibodies may prove beneficial in other endotoxinrelated disorders.

Thesis (Ph.D.)-University of Natal, Durban, 1988.