Cyclooxygenase-2 inhibitor NS-398 improves survival and restores leukocyte counts in burn infection.
BACKGROUND
Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prostaglandin E2 (PGE2) from activated macrophages. PGE2 is increased during trauma and sepsis and has been implicated as a negative immunomodulator. The objective of this study was to determine the therapeutic benefits of a COX-2 inhibitor (NS-398) on survival and leukocyte production in a murine model of burn sepsis.


METHODS
To determine the in vitro ability of NS-398 to inhibit macrophage production of PGE2, peritoneal elicited macrophages were stimulated for 18 hours with medium alone, endotoxin (ETX) (1 mumol/L), or ETX plus NS-398 (0.3 mumol/L). Macrophage supernatant PGE2 levels were determined by an enzyme immunoassay. To test the in vivo efficacy of NS-398, mice subjected to a 15% dorsal scald burn plus 1,000 colony-forming units of topical Pseudomonas aeruginosa received either 10 mg/kg NS-398 intraperitoneally or placebo 4 to 6 hours after infection and twice daily for 3 days. Survival was measured up to 14 days, and circulating white blood cell (WBC) count and absolute neutrophil count (ANC) were determined 3 days after injury.


RESULTS
Macrophage PGE2 production was significantly increased in the ETX-treated group compared with the medium-alone group, and this increase was completely normalized with the addition of NS-398. NS-398 also augmented WBC count (4,288 +/- 649 vs. 7,866 +/- 435 per mm3; p < 0.01) and ANC (1,068 +/- 255 vs. 3,663 +/- 474 per mm3) after burn infection and attenuated macrophage depression of hematopoietic proliferation. Finally, NS-398 treatment significantly improved survival after burn infection, from 0 to 45.5%.


CONCLUSIONS
Inhibition of the COX-2 isoform of cyclooxygenase with NS-398 inhibited macrophage PGE2 production, restored ANC, and improved survival during burn infection. NS-398, therefore, has potential therapeutic benefits in septic patients who have developed neutropenia.
Burn and Shock Trauma Institute, Loyola University Medical Center, Maywood, IL, USA.
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Shoup
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LK
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Liu
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Shankar
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Gamelli
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology* / Q000276:immunology; D002056:Burns / Q000150:complications*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007958:Leukocyte Count / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009578:Nitrobenzenes / Q000627:therapeutic use*; D011897:Random Allocation; D013449:Sulfonamides / Q000627:therapeutic use*; D016019:Survival Analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015232:Dinoprostone