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P-selectin-deficient mice are protected from PAF-induced shock, intestinal injury, and lethality
1Department of Pathology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614, USA.
Abstract:
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.
Insights
Platelet-activating factor (PAF) causes severe injury in mice, but P-selectin deficiency completely protects against these effects. This highlights P-selectin
Area of Science:
- Immunology
- Inflammation Research
- Vascular Biology
Background:
- Platelet-activating factor (PAF) is a potent mediator of inflammation and shock.
- Previous studies in rats indicated anti-CD11b/CD18 antibodies attenuated PAF-induced injury, while anti-P-selectin was ineffective.
Purpose of the Study:
- To elucidate the precise mechanism of PAF-induced injury in vivo using genetically modified mice.
- To investigate the roles of P-selectin, CD18, and intercellular adhesion molecule 1 (ICAM-1) in PAF-mediated responses.
Main Methods:
- Utilized genetically altered mice, including P-selectin-deficient, CD18-deficient, and ICAM-1-deficient strains.
- Administered PAF to these mice and assessed outcomes such as mortality, intestinal injury, hypotension, and hemoconcentration.
- Employed neutrophil depletion and fucoidin pretreatment in specific mouse models.
Main Results:
- P-selectin-deficient mice were fully protected from PAF-induced mortality and intestinal injury, showing only mild hemoconcentration and transient hypotension.
- CD18- or ICAM-1-deficient mice were not protected from PAF-induced tissue injury and death.
- Neutrophil depletion protected against intestinal injury but not hypotension or hemoconcentration.
- Fucoidin pretreatment in ICAM-1-deficient mice significantly reduced PAF's adverse effects, improving survival.
Conclusions:
- P-selectin plays a critical role in mediating PAF-induced tissue injury in mice.
- The selectin and integrin-ICAM-1 systems function collaboratively in the inflammatory cascade triggered by PAF.
- PAF induces granulocytosis, suggesting a role for granulopoiesis in its inflammatory effects.