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 markedly attenuated platelet-activating factor (PAF)-induced shock and intestinal necrosis in rats, whereas anti-P-selectin anti-body was ineffective. 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 intestinal injury and only mild hemoconcentration and transient hypotension. In contrast, CD18- or intercellular adhesion molecule 1 (ICAM-1)-deficient 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; survival was 100%, although hypotension still developed. Neutrophil-depleted mice were protected from PAF-induced intestinal injury but still developed hypotension and hemoconcentration. PAF increases peripheral blood neutrophil counts, probably by inducing granulopoiesis, since neutrophil-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 mediate the inflammatory response to PAF in vivo.
Sun
X
X
Department of Pathology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614, USA.
Rozenfeld
R A
RA
Qu
X
X
Huang
W
W
Gonzalez-Crussi
F
F
Hsueh
W
W
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D018821:CD18 Antigens / Q000502:physiology; D003643:Death; D007022:Hypotension / Q000139:chemically induced; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology; D007421:Intestine, Small / Q000473:pathology; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009336:Necrosis; D019007:P-Selectin / Q000235:genetics / Q000502:physiology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011134:Polysaccharides / Q000494:pharmacology; D051381:Rats; D012769:Shock / Q000503:physiopathology* / Q000517:prevention & control; D013045:Species Specificity
D000925:Anticoagulants; D018821:CD18 Antigens; D019007:P-Selectin; D010972:Platelet Activating Factor; D011134:Polysaccharides; D018799:Intercellular Adhesion Molecule-1; C007789:fucoidan