M. Shoup et al., CYCLOOXYGENASE-2 INHIBITOR NS-398 IMPROVES SURVIVAL AND RESTORES LEUKOCYTE COUNTS IN BURN INFECTION, The journal of trauma, injury, infection, and critical care, 45(2), 1998, pp. 215-220
Background: Cyclooxygenase-2 (COX-2) is a key enzyme in the production
of prostaglandin E-2 (PGE(2)) from activated macrophages, PGE(2) is i
ncreased during trauma and sepsis and has been implicated as a negativ
e immunomodulator, The objective of this study was to determine the th
erapeutic benefits of a COX-2 inhibitor (NS-398) on survival and leuko
cyte production in a murine model of burn sepsis. Methods: To determin
e the in vitro ability of NS-398 to inhibit macrophage production of P
GE(2), peritoneal elicited macrophages were stimulated for 18 hours wi
th 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 subj
ected to a 15% dorsal scald burn plus 1,000 colony-forming units of to
pical Pseudomonas aeruginosa received either 10 mg/kg NS-398 intraperi
toneally or placebo 4 to 6 hours after infection and twice daily for 3
days. Survival was measured up to 14 days, and circulating white bloo
d cell (WBC) count and absolute neutrophil count (ANC) were determined
3 days after injury. Results: Macrophage PGE(2) production was signif
icantly increased in the ETX-treated group compared with the medium-al
one group, and this increase was completely normalized with the additi
on 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 significantl
y improved survival after burn infection, from 0 to 45.5%. Conclusion:
Inhibition of the COX-2 isoform of cyclooxygenase with NS-398 inhibit
ed macrophage PGE(2) production, re stored ANC, and improved survival
during burn infection. NS-398, therefore, has potential therapeutic be
nefits in septic patients who have developed neutropenia.