Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans
- Conditions
- Endotoxemia
- Registration Number
- NCT00246714
- Lead Sponsor
- Radboud University Medical Center
- Brief 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.
- Detailed Description
See protocol
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 16
- Healthy male volunteers
- drug-, nicotine-, alcohol abuses
- tendency towards fainting
- BMI < 18 kg/m2
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method inducing endotoxin tolerance 5 days Hemodynamics 5 days Markers of Inflammation 5 days Cytokines 5 days Mediators of Vascular reactivity 5 days Sensitivity to norepinephrine 5 days Endothelial-dependent vasorelaxation 5 days Cross tolerance 6 days Ischemia-reperfusion injury 6 days Effects on tissue saturation (measured by NIRS) 24 hrs after LPS administration
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
Radboud University Nijmegen Medical Center
🇳🇱Nijmegen, Gelderland, Netherlands