INCREASED P-SELECTIN GENE-EXPRESSION IN THE LIVER VASCULATURE AND ITSROLE IN THE PATHOPHYSIOLOGY OF NEUTROPHIL-INDUCED LIVER-INJURY IN MURINE ENDOTOXIN-SHOCK

We studied the role of P-selectin, an adhesion molecule known to be im portant for neutrophil localization to sites of inflammation, in a mod el of inflammatory liver injury. Male C3Heb/FeJ (ET-sensitive) mice tr eated with 700 mg/kg galactosamine and 100 mu g/kg Salmonella abortus equi endotoxin (Gal/ET), murine tumor necrosis factor alpha (TNF-alpha , 15 mu g/kg), or interleukin-1 (IL-1, 13-23 mu g/kg), showed increase d P-selectin mRNA levels in the liver. In contrast, C3H/HeJ (ET-resist ant) mice responded only to cytokines with P-selectin mRNA formation. Whereas no P-selectin expression was detectable in control livers, the re was temporary staining of endothelium in large blood vessels but no t in sinusoids between 3 and 5 h after ET, TNF-alpha, or IL-1 treatmen t. Severe liver injury induced by Gal/ET at 7 h was not inhibited by a n anti-P-selectin antibody in C3Heb/FeJ mice or in P-selectin-deficien t animals. Sequestration of neutrophils in sinusoids, i.e. those neutr ophils that have been identified as critical for the injury, was not a ffected by the antibody or in P-selectin-deficient mice, However, the temporary margination in portal and post-sinusoidal venules was reduce d by 75% in anti-P-selectin antibody-treated animals and by 51% in P-s electin-deficient mice. We conclude that hepatic P-selectin gene trans cription in vivo involves cytokines. However, blocking P-selectin neit her attenuated sinusoidal neutrophil sequestration nor prevented neutr ophil-induced liver injury during endotoxin shock but attenuated neutr ophil margination in larger vessels. Thus, our data demonstrate simila rities and fundamental differences in the requirement for adhesion mol ecules to localize neutrophils in the liver vasculature compared to ot her organs during an inflammatory response.