Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans
Status:
Completed
Trial end date:
2007-12-01
Target enrollment:
Participant gender:
Summary
A number of diseases lead to a so called systemic inflammatory response syndrome (SIRS). This
excessive response is self-destructive and leads to major complications of the initial
disease: dysfunction of the microcirculation, systemic vasodilation, and increased capillary
leakage and oedema. Animal studies have shown that pre-treatment with endotoxin
(lipopolysaccharide or LPS) suppress the excessive immune response and when rechallenged, the
animal survive a normally lethal dose of endotoxin.
Besides a diminished cytokine response, an increased production of leucocytes in the bone
marrow and an increased phagocytosis after pre-treatment with endotoxin is seen. The
combination of these factors: diminished systemic inflammatory response and increased
cellular immunity makes that endotoxin tolerance is a useful tool for preventing the
complications after an excessive inflammatory response.
Further, the presence of cross-tolerance has also been shown: Endotoxin tolerant mice survive
more after induction of a normally lethal fungal infection. Endotoxin tolerance is also
protective for ischemia/reperfusion injury in kidneys, heart and liver. Little data is known
about endotoxin tolerance in human.
The purpose of this study is to induce a state of tolerance through 2 different
administration schedules and monitor the effect of tolerance on pro- and anti-inflammatory
cytokines, other inflammatory parameters and different proteins involved in the signalling
pathway. The effects of tolerance on vascular reactivity will be determined. Finally, the
effect of tolerance on ischemia-reperfusion injury will be investigated.