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.
Kamochi
M
M
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA.
Kamochi
F
F
Kim
Y B
YB
Sawh
S
S
Sanders
J M
JM
Sarembock
I
I
Green
S
S
Young
J S
JS
Ley
K
K
Fu
S M
SM
Rose
C E
CE
D000818:Animals; D001773:Blood Cells / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D004731:Endotoxins / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology*; D007958:Leukocyte Count / Q000187:drug effects; D007962:Leukocytes / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000473:pathology / Q000502:physiology*; D019007:P-Selectin / Q000378:metabolism / Q000502:physiology*; D011652:Pulmonary Circulation / Q000502:physiology; D012709:Serum Albumin / Q000378:metabolism; D007507:Therapeutic Irrigation
D004731:Endotoxins; D008070:Lipopolysaccharides; D019007:P-Selectin; D012709:Serum Albumin; D018799:Intercellular Adhesion Molecule-1