Platelet-activating factor produces shock, in vivo complement activation, and tissue injury in mice.
We previously showed that TNF and endotoxin (LPS) synergize to activate the complement system and produce shock and bowel injury in normal mice. However, C5-deficient mice were protected from these adverse effects. In this study, we show that in mice, platelet-activating factor (PAF) antagonist prevents TNF- and LPS-induced complement activation, bowel injury, and death, indicating that PAF mediates the actions of TNF and LPS. We then examined the role of the complement system in PAF-induced shock and tissue injury. We found that 1) PAF (3 micrograms/kg) induces shock, hemoconcentration, bowel necrosis, and death in normal mice, whereas C5-deficient mice are protected from these effects. (Protection was abrogated when the dose of PAF was raised to 5 micrograms/kg.) Furthermore, when C5-deficient mice were reconstituted with normal serum, they also developed shock, bowel injury, and death in response to PAF. Thus, C5 is required for PAF to induce injury. 2) PAF activates the complement system in vivo, but not in vitro. The mechanism of complement activation by PAF is unclear. Inasmuch as PAF stimulates neutrophils to release protease that may activate the complement system, we examined the effect of neutrophil depletion on PAF-induced injury and complement activation. We found that neutrophil depletion fails to prevent PAF-induced complement activation, although PAF-induced lethality is much reduced. We conclude that PAF causes complement activation, and acts in synergy with active complement fragments to produce shock and tissue injury. Neutrophils probably do not play the pivotal role in PAF-induced complement activation.
Sun
X M
XM
Department of Pathology, Children's Memorial Hospital, Northwestern University Medical School, Chicago, IL 60614.
Hsueh
W
W
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects*; D003182:Complement C5 / Q000172:deficiency; D004305:Dose-Response Relationship, Drug; D006400:Hematocrit; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000473:pathology; D007958:Leukocyte Count / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008817:Mice, Mutant Strains; D009336:Necrosis; D009504:Neutrophils / Q000502:physiology; D010972:Platelet Activating Factor / Q000494:pharmacology*; D012769:Shock / Q000139:chemically induced*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000633:toxicity*; D014747:Vinblastine / Q000494:pharmacology
D003182:Complement C5; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D014747:Vinblastine