ENDOGENOUSLY OPSONIZED PARTICLES DIVERT PROSTANOID ACTION FROM LETHALTO PROTECTIVE IN MODELS OF EXPERIMENTAL ENDOTOXEMIA

We report that, in rats, the lethal consequences of high-dose endotoxi n challenge are exacerbated by the intravascular administration of pro staglandin E(1) but attenuated by the intravascular administration of endocytosable particles. This protection is mediated by opsonins. Nono psonizable particles were unable to provide protection unless first ps eudoopsonized with antibody directed against the CR3 (CD11b/CD18) phag ocyte receptor. We show that endogenously opsonized particles can act in concert with prostaglandin E(1) (putatively by elevation of neutrop hil intracellular cAMP and the resultant downregulation of CR3) to com pletely rescue animals from the lethal late-stage sequelae of experime ntal endotoxemia. These data illustrate that the interaction of partic les with cellular receptors can transform the overall systemic respons e to prostaglandin E(1) from pro- to antiinflammatory. This suggests a role for multiple receptor engagement events in defining the systemic prostaglandin response and offers a rationale for developing new ther apeutic modalities in the treatment of sepsis and other inflammatory d iseases.