NITRIC-OXIDE INHIBITION NORMALIZES SPLENOCYTE INTERLEUKIN-10 SYNTHESIS IN MURINE THERMAL-INJURY

Objective: To examine the effect of nitric oxide inhibition on cytokin e production and immunologic function in a murine thermal-injury and a n alcohol (ETOH) -ingestion model. Design: Randomized controlled exper iment. Setting: University surgical research laboratory. Animals: Fort y male Balb/C mice. Interventions: Animals were randomized to four gro ups: normal saline solution-sham (NS-sham), ETOH-sham, NS-burn, and ET OH-burn. Animals received 20% ETOH or NS daily for 14 days by gavage. A 20% full-thickness burn was induced 4 hours after the last dose of E TOH or NS was administered. Animals were killed 4 days after the burn was induced. Main Outcome Measures: Splenocytes were harvested and sti mulated with the mitogens lipopolysaccharide or con-canavalin A. These mitogen-stimulated splenoctye cultures had the addition of exogenous N-monomethyl-L-arginine (2.5 or 10 mu g/mL), a nitric oxide synthase i nhibitor. Splenocyte production of interleukin-10 (IL-10), interferon- gamma, nitrite, and prostaglandin E(2) were measured, and lymphocyte p roliferative response was examined. Results: Interleukin-10 and interf eron-gamma production were significantly suppressed in thermal injury, and lymphocyte proliferative response was markedly reduced. Exogenous N-monomethyl-L-arginine normalized splenocyte IL-10 production in a d ose-dependent manner in NS-burn and ETOH-burn groups, improved lymphoc yte proliferative response, and significantly decreased splenocyte nit rite production. Interferon-gamma release was not up-regulated by N-mo nomethyl-L-arginine. Conclusions: Thermal injury is associated with a suppression of splenocyte IL-10 production and lymphocyte proliferativ e response. Inhibition of nitric oxide synthesis normalized IL-10 prod uction and significantly improved splenocyte proliferative response. T hese data suggest that nitric oxide is an important modulator of cytok ine regulation and immunologic function in thermal injury, thereby ult imately influencing host defense.