Modulation of macrophage hyperactivity improves survival in a burn-sepsis model
M. G. O'Riordain, K. H. Collins, M. Pilz, I. B. Saporoschetz, J. A. Mannick and M. L. Rodrick
Department of Surgery, Brigham & Women's Hospital, Harvard Medical School, Boston, Mass. 02115.
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 1 beta
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 alpha production were all significantly
increased 10 days after thermal injury. Treatment with recombinant human
interleukin 1 beta 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 beta-indomethacin-treated group compared with 22% in burned
vehicle control mice). Burned mice that received either interleukin 1 beta
or indomethacin alone demonstrated tumor necrosis factor and interleukin 6
production and survival intermediate between the interleukin 1
beta-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.
