Endotoxemia
Conditions
Keywords
endotoxin tolerance, humans, cross-tolerance, pro and anti-inflammatory cytokines
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
Interventions
DRUGrepeated injections of endotoxin during 5 days
Sponsors
Radboud University Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male volunteers
Exclusion criteria
* drug-, nicotine-, alcohol abuses * tendency towards fainting * BMI \< 18 kg/m2
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 |
Countries
Netherlands
Outcome results
None listed