Endogenously opsonized particles divert prostanoid action from lethal to protective in models of experimental endotoxemia.
We report that, in rats, the lethal consequences of high-dose endotoxin challenge are exacerbated by the intravascular administration of prostaglandin E1 but attenuated by the intravascular administration of endocytosable particles. This protection is mediated by opsonins. Nonopsonizable particles were unable to provide protection unless first pseudoopsonized with antibody directed against the CR3 (CD11b/CD18) phagocyte receptor. We show that endogenously opsonized particles can act in concert with prostaglandin E1 (putatively by elevation of neutrophil intracellular cAMP and the resultant downregulation of CR3) to completely rescue animals from the lethal late-stage sequelae of experimental endotoxemia. These data illustrate that the interaction of particles with cellular receptors can transform the overall systemic response to prostaglandin E1 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 therapeutic modalities in the treatment of sepsis and other inflammatory diseases.
Eierman
D F
DF
Liposome Company, Inc., Princeton, NJ 08540-6619, USA.
Yagami
M
M
Erme
S M
SM
Minchey
S R
SR
Harmon
P A
PA
Pratt
K J
KJ
Janoff
A S
AS
D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D018845:CD11 Antigens / Q000276:immunology / Q000502:physiology*; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D000242:Cyclic AMP / Q000097:blood*; D004195:Disease Models, Animal; D004926:Escherichia coli; D005434:Flow Cytometry; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D008081:Liposomes / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009895:Opsonin Proteins; D010587:Phagocytosis; D010713:Phosphatidylcholines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014115:Toxemia / Q000503:physiopathology*
D018845:CD11 Antigens; D018821:CD18 Antigens; D008070:Lipopolysaccharides; D008081:Liposomes; D009895:Opsonin Proteins; D010713:Phosphatidylcholines; D000242:Cyclic AMP; D000527:Alprostadil