Blockade of prostaglandin products augments macrophage and neutrophil tumor necrosis factor synthesis in burn injury.
Cyclooxygenase products are believed to be a major regulator of host tumor necrosis factor-alpha (TNF-alpha) production in response to trauma and sepsis. To study this relationship, Lewis rats underwent a 30% burn or sham burn. Dimethyl-prostaglandin E (dPGE, 50 micrograms/kg), ibuprofen (IFU, 2 mg/kg), or saline was administered twice daily. Rats were sacrificed at Day 7 to obtain Kupffer cells, peritoneal macrophages, splenic macrophages, and neutrophils. For in vivo studies, 10(6) cells from each group were cultured with 10 micrograms of lipopolysaccharide (LPS). For in vitro studies, cells from the burn and sham groups were cultured with LPS and dPGE (10 micrograms/ml), IBU (10 micrograms/ml), or saline. The supernatants were harvested after 2, 6, and 24 hr of culture and assayed for TNF-alpha (mu/ml) by L929 cytolysis. Burn injury resulted in a significant increase in Kupffer cell and neutrophil TNF-alpha production compared to the sham group (P < 0.001, ANOVA). The administration of IBU to burned animals led to a pronounced elevation of TNF-alpha production by Kupffer cells, peritoneal macrophages, and neutrophils compared to vehicle-treated burned animals (P < 0.001, ANOVA). With in vitro studies, IBU increased Kupffer cell, peritoneal macrophage, and neutrophil TNF-alpha release by 213, 327, and 198%, respectively (P < 0.05, ANOVA). dPGE caused a marked decrease in Kupffer cell and peritoneal macrophage TNF-alpha synthesis by 50 and 43%, respectively (P < 0.01, ANOVA). In conclusion, prostaglandins are critical for down regulating TNF-alpha production. Clinical use of cyclooxygenase inhibitors may result in adverse outcomes due to the excessive TNF-alpha production.
Dong
Y L
YL
Shriners Burns Institute, Galveston Unit, University of Texas Medical Branch 77550.
Herndon
D N
DN
Yan
T Z
TZ
Waymack
J P
JP
D000818:Animals; D002056:Burns / Q000378:metabolism*; D007052:Ibuprofen / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000378:metabolism*; D011453:Prostaglandins / Q000502:physiology*; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D011453:Prostaglandins; D011459:Prostaglandins E, Synthetic; D014409:Tumor Necrosis Factor-alpha; C017244:16,16-dimethylprostaglandin E; D007052:Ibuprofen