The hepatic microvascular alterations in polymicrobial sepsis are not mediated by bacterial endotoxin.

Although sepsis remains a leading cause of death in critically ill patients, the mechanisms underlying this disease process remain undefined. Because bacterial endotoxin (LPS) is widely held to be a mediator of the inflammatory events associated with sepsis, LPS administration is often used to simulate sepsis in experimental animals. The objective of this study was to test the hypothesis that LPS is a critical determinant of the hepatic microvascular alterations induced by cecal ligation and puncture (CLP), a widely used model of experimental sepsis. Hepatic sinusoidal perfusion and the adhesion of platelets and leukocytes in terminal hepatic venules (THV) and sinusoids were quantified by intravital microscopy in LPS‐sensitive and LPS‐insensitive mice subjected either to CLP or i.p. administration of LPS. Both CLP and LPS‐administration elicited increases in the adhesion of both leukocytes and platelets in THV and sinusoids with corresponding reductions in the density of perfused sinusoids in LPS‐sensitive mice. However, a dose of 500 ?g/kg LPS was required to elicit hepatic microvascular changes of comparable magnitude to CLP in LPS‐sensitive mice. While LPS‐insensitive mice exhibited the same leukocyte and platelet adhesion (in both THV and sinusoids) and sinusoidal malperfusion responses to CLP, these mice were unresponsive to exogenous LPS‐administration at doses of 50 and 500 μg/kg. These findings do not support a major role for bacterial endotoxin in the hepatic microvascular disturbances associated with polymicrobial sepsis. Supported by P01 DK43785.