Cyclooxygenase-2 Inhibitor NS-398 Improves Survival and Restores Leukocyte Counts in Burn Infection
| Autor: | Richard L. Gamelli, Margo Shoup, Li Ke He, Hong Liu, Ravi Shankar |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Male
medicine.medical_treatment Drug Evaluation Preclinical Mice Inbred Strains Pharmacology Neutropenia Dinoprostone Sepsis Leukocyte Count Mice Random Allocation In vivo White blood cell medicine Animals Cyclooxygenase Inhibitors Prostaglandin E2 Nitrobenzenes Sulfonamides biology business.industry Anti-Inflammatory Agents Non-Steroidal Bacterial Infections medicine.disease Survival Analysis Disease Models Animal medicine.anatomical_structure Immunology Macrophages Peritoneal Absolute neutrophil count biology.protein Cyclooxygenase Burns business Prostaglandin E medicine.drug |
| Zdroj: | The Journal of Trauma: Injury, Infection, and Critical Care. 45:215-221 |
| ISSN: | 1079-6061 |
| DOI: | 10.1097/00005373-199808000-00003 |
| Popis: | 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 μmol/L), or ETX plus NS-398 (0.3 μmol/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, restored ANC, and improved survival during burn infection. NS-398, therefore, has potential therapeutic benefits in septic patients who have developed neutropenia. |
| Databáze: | OpenAIRE |
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