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 E-2 (PGE(2)) from activated macrophages, PGE(2) 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 PGE(2), peritoneal elicited macrophages were stimulated for 18 hours with medium alone, endotoxin (ETX) (1 mu mol/L), or ETX plus NS-398 (0.3 mu mol/L). Macrophage supernatant PGE(2) 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 PGE(2) 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 mm(3); p < 0.01) and ANC (1,068 +/- 255 vs, 3,663 +/- 474 per mm(3)) 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%. Conclusion: Inhibition of the COX-2 isoform of cyclooxygenase with NS-398 inhibited macrophage PGE(2) production, re stored ANC, and improved survival during burn infection. NS-398, therefore, has potential therapeutic benefits in septic patients who have developed neutropenia.