P-SELECTIN-DEFICIENT MICE ARE PROTECTED FROM PAF-INDUCED SHOCK, INTESTINAL INJURY, AND LETHALITY

In a previous study, we showed that anti-CD11b or anti-CD18 antibody m arkedly attenuated platelet-activating factor (PAF)-induced shock and intestinal necrosis in rats, whereas anti-P-selectin antibody was inef fective. Here we used genetically altered mice to study the mechanism of PAF in mice. We found that P-selectin-deficient mice are completely protected from the adverse effects of PAF with no mortality or intest inal injury and only mild hemoconcentration and transient hypotension. In contrast, CD18- or intercellular adhesion molecule 1 (ICAM-1)-defi cient mice were not protected from PAF-induced tissue injury and death . However when ICAM-1-, but not CD18-, deficient mice were pretreated with fucoidin, the adverse effects of PAF were markedly reduced; survi val was 100%, although hypotension still developed. Neutrophil-deplete d mice were protected from PAF-induced intestinal injury but still dev eloped hypotension and hemoconcentration. PAF increases peripheral blo od neutrophil counts, probably by inducing granulopoiesis, since neutr ophil-depleted mice still showed granulocytosis 60 min after PAF. Thus P-selectin plays an important role in PAF-induced injury in mice, and the selectins and the integrin-ICAM-1 system work in concert to media te the inflammatory response to PAF in vivo.