MECHANISM OF INCREASED TUMOR-NECROSIS-FACTOR PRODUCTION AFTER THERMAL-INJURY - ALTERED SENSITIVITY TO PGE(2) AND IMMUNOMODULATION WITH INDOMETHACIN

Altered macrophage function after thermal injury is associated with in creased production of PGE2 and TNF. However, it is not clear why synth esis of both cellular products remains elevated, as PGE2 is a potent i nhibitor of TNF secretion. We studied the relationship between PGE2 an d TNF synthesis in a murine model of thermal injury, and examined the effect of prostaglandin blockade on splenic macrophage secretion of th ese mediators of inflammation. LPS-stimulated production of PGE2 was s ignificantly elevated in burn groups compared with sham-burned control s (pg/ml mean(SEM); sham 151(32): burn 597(147), p <0.01). TNF product ion was similarly increased after thermal injury (pg/ml mean(SEM); sha m 62(20): burn 928(316), p <0.01). In vitro culture of macrophages wit h indomethacin augmented LPS stimulated TNF production in sham-burned controls but did not affect synthesis in burn groups, suggesting a los s of PGE2-dependent regulation of TNF synthesis after thermal injury. Direct measurement of TNF secretion as a function of exogenous PGE2 co nfirmed this dissociation between PGE2 and TNF synthesis, as burned an imals displayed a 5-fold reduction in sensitivity to PGE2-induced inhi bition of TNF, when compared with sham-burned controls (ID50 PGE2 mola r; sham 1.26 x 10(-8): burn 6.43 x 10(-8), p <0.05). In vivo pretreatm ent of burn groups with indomethacin for 5 days before assay partially restored sensitivity to the prostaglandin, and significantly down-reg ulated synthesis of both TNF and PGE2. These data show that thermal in jury is associated with a loss of PGE2-dependent down-regulation of TN F synthesis, which accounts at least in part for increased TNF in thes e animals. In vivo cyclooxygenase blockade partially restored sensitiv ity to the prostaglandin and consequently down-regulated synthesis of TNF. These data further support existing evidence that suggests a pote ntial therapeutic role for cyclooxygenase blockade after major thermal injury and trauma.