NS-398 Treatment after Trauma Modifies NF-κB Activation and Improves Survival

• Published in: The Journal of surgical research Vol. 98; no. 1; pp. 40 - 46
• Main Authors: Mack Strong, V.E., Mackrell, P.J., Concannon, E.M., Mestre, J.R., Smyth, Gordon P., Schaefer, P.A., Stapleton, P.P., Daly, J.M.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01-06-2001; Elsevier
• Subjects: Biological and medical sciences; cecal ligation and puncture; COX-2; COX-2 inhibitor; cytokines; fracture; gram-negative sepsis; hemorrhage; infection; injury; IκB; Medical sciences; mice; Miscellaneous; sepsis; shock; Traumas. Diseases due to physical agents; gram-negative sepsis; COX-2 inhibitor; infection; COX-2; shock; mice; fracture; IκB; cytokines; injury; sepsis; hemorrhage; cecal ligation and puncture; Arachidonic acid derivatives; Rodentia; Prostaglandin E2; NS-398 treatment; Experimental study; Survival; Trauma; Vertebrata; Improvement; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Biological effect
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.2001.6154

Prostaglandin E2 (PGE2) production after trauma contributes to immune alterations that increase susceptibility to infections. We hypothesize that blocking PGE2 with NS-398, a selective COX-2 inhibitor, will modulate this response and improve outcome. This study evaluated the effect of NS-398 given over 7 days on proinflammatory cytokines, intracellular signaling, and survival after a septic challenge.
Balb/C mice (n = 8/group) were given 10 mg/kg NS-398 intraperitoneally over 7 days, starting after anesthesia or trauma (femur fracture + 40% hemorrhage). Four groups, anesthesia + vehicle (C), anesthesia + NS-398 (CN), trauma + vehicle (T), or trauma + NS-398 (TN), were studied. On Day 7 after trauma, mice were sacrificed, serum was collected, and splenic macrophages were evaluated for PGE2, LTB4, IL-6, TNF-α, and NO production. Additionally, macrophage COX-2 mRNA, IκB-α, and NF-κB were evaluated. In a separate study, mice (n = 10–11/group) were traumatized and given NS-398 over 7 days, and then cecal ligation and puncture (CLP) were performed. Mice were then followed for survival over 10 days (via log-rank test).
NS-398 treatment of injured mice decreased PGE2 production compared to T (3.9 ± 0.3 vs 3.1 ± 0.4 pg/μg protein), and significantly decreased IL-6, NO, and TNF-α production. NS-398 treatment also attenuated COX-2 mRNA levels and NF-κB activation. These cellular events correlate with a significant survival advantage in TN versus T mice after CLP.
These data suggest that a specific COX-2 inhibitor not only suppresses PGE2, but normalizes proinflammatory cytokines after trauma through changes that may partly be mediated via transcriptional events. This correlates with significantly increased survival in TN mice given a septic challenge and suggests that COX-2 inhibitors contribute to modulating the inflammatory response and improving survival after trauma.