DOES ENDOTOXIN PLAY A MAJOR ROLE IN INDUCING THE DEPRESSION OF MACROPHAGE FUNCTION DURING POLYMICROBIAL SEPSIS

Background: Endotoxin (ETX) is thought to be the primary inducer of pr oinflammatory mediator release associated with bacterial sepsis. Furth ermore, a number of studies indicate that preexposure of animals to hi gh doses of ETX produces macrophages (M phi s) that are refractory to ex vivo stimulation with ETX. However, it is unknown if levels of ETX comparable to those typically encountered in sepsis induce a similar r efractory state in M phi s. Design: To assess this, peritoneal M phi s (PM phi s) were harvested from C3H/HeN mice (ETX sensitive) at 1 hour (early) or 24 hours (late) following cecal ligation and puncture (CLP ) to induce polymicrobial sepsis, sham CLP, or laparotomy followed by peritoneal implantation of a minipump delivering either saline or ETX (0.025 mu g/g of body weight, every 24 hours). Peritoneal M phi cultur es were incubated with ETX, either 0 or 10 mu g/mL, for 24 hours, and their ability to release interleukin-1, interleukin-6, and tumor necro sis factor was assessed by bioassay. Results: Chronic low-dose ETX wit h 0 mu g of ETX media added produced early (at 1 hour) in vivo activat ion of PM phi interleukin-1 release, which was comparable to that seen in mice subjected to CLP. However, unlike PM phi s taken from CLP mic e, PM phi s from mice implanted with the ETX minipump at 1 or 24 hours showed no marked decline in their ability to respond to ETX (10 mu g) . Comparable changes were seen for interleukin-6 and tumor necrosis fa ctor release. Conclusions: Bacterial component(s) other than ETX per s e induces the sustained dysfunction in PM phi capacity to produce proi nflammatory cytokines during sepsis and/or peritonitis. Thus, agents d irected against ETX alone may not be adequate in the treatment of poly microbial sepsis.