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Tolerance to low-dose endotoxin in awake sheep
R I Whyte1, H S Warren, E Greene
1Department of Surgery, Harvard Medical School, Massachusetts General Hospital, Boston 02114.
Journal of Applied Physiology (Bethesda, Md. : 1985)
|June 1, 1989
Summary
Small intravenous doses of lipopolysaccharide (LPS) in sheep trigger significant physiological responses and tolerance. Repeated or large LPS doses can diminish these effects, impacting hemodynamic and eicosanoid mediator responses.
Area of Science:
- Immunology
- Physiology
- Pharmacology
Background:
- Lipopolysaccharide (LPS) from Serratia marcescens is a potent endotoxin.
- Understanding LPS dose-response and tolerance is crucial for sepsis research.
Purpose of the Study:
- To investigate the dose-response effects of intravenous LPS in awake sheep.
- To examine the development of acute and chronic tolerance to LPS.
Main Methods:
- Administered varying doses of S. marcescens LPS intravenously to awake sheep.
- Monitored core temperature, pulmonary arterial pressure, vascular resistance, thromboxane B2, 6-keto-prostaglandin F1 alpha, and leukocyte counts.
- Assessed tolerance by repeated daily injections and a chronic dosing regimen.
Main Results:
- Small LPS doses (0.002-0.2 µg/kg) induced dose-dependent increases in temperature, pulmonary pressure, thromboxane B2, and prostaglandin F1 alpha, along with leukopenia.
- Acute tolerance developed by the third daily dose, reducing pulmonary and thromboxane responses.
- Chronic LPS administration (0.1-3.2 µg/kg) over 7 weeks resulted in complete tolerance to a subsequent small LPS challenge.
Conclusions:
- Intravenous LPS induces significant pulmonary and systemic physiological changes in sheep.
- Tolerance to LPS effects, both acute and chronic, can be established through repeated or high-dose administration.
- LPS tolerance can ablate responses to subsequent challenges, impacting hemodynamic and mediator profiles.