Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

Study Overview
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Brief Summary
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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
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See protocol

Official Title
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Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

Conditions
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Endotoxemia

Intervention / Treatment
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* Drug: repeated injections of endotoxin during 5 days


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male volunteers Exclusion Criteria: drug-, nicotine-, alcohol abuses tendency towards fainting BMI < 18 kg/m2

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: repeated injections of endotoxin during 5 days|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cross-tolerance, endotoxin tolerance, humans, pro and anti-inflammatory cytokines