Cyclooxygenase-2 inhibitor NS-398 improves survival and restores leukocyte counts in burn infection

Margo Shoup, Li Ke He, Hong Liu, Ravi Shankar, Richard Gamelli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

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 μmol/L), or ETX plus NS-398 (0.3 μmol/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%. Conclusion: Inhibition of the COX-2 isoform of cyclooxygenase with NS- 398 inhibited macrophage PGE2 production, restored ANC, and improved survival during burn infection. NS398, therefore, has potential therapeutic benefits in septic patients who have developed neutropenia.

Original languageEnglish (US)
Pages (from-to)215-221
Number of pages7
JournalJournal of Trauma - Injury, Infection and Critical Care
Volume45
Issue number2
DOIs
StatePublished - Aug 1998

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

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