WEB2170, a specific platelet-activating factor antagonist, attenuates neutrophil priming by human serum after clinical burn injury: the 1991 Moyer Award.
Primed neutrophils may contribute to endothelial and end-organ damage after burn injury because of increased endothelial adherence and enhanced toxic oxygen metabolite generation in response to a "second insult" such as bacterial sepsis. The purposes of this study were to determine: (1) whether serum from patients with thermal injury causes priming of the neutrophil NADPH:O2 oxidoreductase, (2) whether time after burn (early vs late) influences neutrophil priming, and (3) whether priming could be attenuated by a specific platelet-activating factor antagonist, WEB2170. Normal human neutrophils were incubated with 10% sera that was obtained from healthy adult controls (normal human sera) and with 10% sera from patients with greater than 30% total body surface area burns, which was collected early (early postburn sera) (i.e., between 12 and 48 hours after burn) or late (late postburn sera) (5 to 15 days, after burn). Priming of the neutrophil oxidase was tested for by measurement of the generation of superoxide anion after a stimulus of 10(-6) mol/L formyl-methionine-leucine-phenylalanine (fMLP). In separate experiments, neutrophils were pretreated with WEB2170 before serum incubation and fMLP stimulation to block any priming that may be mediated by platelet-activating factor. All sera caused an increased rate of superoxide anion production in response to fMLP and thus "primed" the neutrophil NADPH:O2 oxidoreductase. Greater priming occurred after incubation with late postburn sera than with other sera. WEB2170 completely inhibited priming by normal human sera and early postburn sera and partially inhibited priming by late postburn sera.(ABSTRACT TRUNCATED AT 250 WORDS)
Pitman
J M
JM
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262.
Thurman
G W
GW
Anderson
B O
BO
Ketch
L L
LL
Hartford
C E
CE
Harken
A H
AH
Ambruso
D R
DR
D000328:Adult; D001363:Awards and Prizes; D001381:Azepines / Q000494:pharmacology*; D001830:Body Surface Area; D002056:Burns / Q000097:blood* / Q000150:complications; D013502:General Surgery; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000097:blood*; D019255:NADPH Oxidases; D009504:Neutrophils / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; D013481:Superoxides; C063964:bepafant; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; C022709:superoxide-forming enzyme