Modulation of Macrophage Hyperactivity Improves Survival in a Burn-Sepsis Model

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Abstract
• Macrophage hyperactivity with increased production of tumor necrosis factor, interleukin 6, interleukin 1, and prostaglandins has been demonstrated in the injured patient, but the effect of this on the clinical outcome is unclear. We studied the effect of combination interleukin 1β and indomethacin sodium therapy on macrophage hyperactivity and survival after sepsis in a murine burn model. Macrophage interleukin 1, interleukin 6, and tumor necrosis factor α production were all significantly increased 10 days after thermal injury. Treatment with recombinant human interleukin 1 β in combination with indomethacin significantly reduced this overproduction of cytokines to normal levels, and this was associated with an improvement in survival after septic challenge (52% survival in interleukin 1 β–indomethacin—treated group compared with 22% in burned vehicle control mice). Burned mice that received either interleukin 1 β or indomethacin alone demonstrated tumor necrosis factor and interleukin 6 production and survival intermediate between the interleukin 1β—indomethacin—treated group and the vehicle control group. Control of macrophage hyperactivity is associated with improved survival from subsequent sepsis and offers a potential new strategy for the treatment of immune dysfunction in thermally injured patients. (Arch Surg. 1992;127:152-158)