P-selectin and ICAM-1 mediate endotoxin-induced neutrophil recruitment and injury to the lung and liver.

The role of leukocyte adhesion molecules in endotoxin-induced organ injury was evaluated by administering intraperitoneal Salmonella enteritidis lipopolysaccharide (LPS) to wild-type (WT) mice, P-selectin-deficient mice, intercellular adhesion molecule (ICAM)-1-deficient mice, and P-selectin-ICAM-1 double-mutant mice. In WT mice, there was a sevenfold increase in the number of neutrophils present in the pulmonary vascular lavage fluid, and there were sevenfold more intracapillary neutrophils by electron-microscopic (EM) morphometry at 4 h after intraperitoneal LPS compared with that in control mice. Extravascular albumin accumulation increased approximately twofold in the lungs and liver of WT mice treated with LPS. In the double-mutant mice, although overall mortality after intraperitoneal LPS was not attenuated, there was a significant delay in mortality in the P-selectin-ICAM-1-deficient mutants compared with that in WT mice after intraperitoneal LPS (P < 0.01). Moreover, compared with LPS-treated WT mice, lung and liver extravascular albumin accumulation was significantly lower in LPS-treated P-selectin-ICAM-1 double-mutant mice. Lung myeloperoxidase activity, normalized per 1,000 circulating neutrophils, increased after endotoxin in WT and P-selectin-deficient mice but not in P-selectin-ICAM-1 double-mutant mice. In addition, lung and liver myeloperoxidase activity per 1,000 circulating neutrophils in endotoxin-treated ICAM-1-deficient mice and P-selectin-ICAM-1 double mutants was significantly lower compared with that in endotoxin-treated WT mice. These data suggest that P-selectin and ICAM-1 significantly contribute to lung and liver injury after systemic endotoxemia.