Does endotoxin play a major role in inducing the depression of macrophage function during polymicrobial sepsis?
A. Ayala, Z. K. Deol, D. L. Lehman, C. D. Herdon and I. H. Chaudry
Department of Surgery, Michigan State University, East Lansing, USA.
BACKGROUND: Endotoxin (ETX) is thought to be the primary inducer of
proinflammatory mediator release associated with bacterial sepsis.
Furthermore, a number of studies indicate that preexposure of animals to
high doses of ETX produces macrophages (M luminal diameters) 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 refractory state in M luminal diameters. DESIGN: To assess this,
peritoneal M luminal diameters (PM luminal diameters) 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 microgram/g of body weight, every 24 hours).
Peritoneal M luminal diameter cultures were incubated with ETX, either 0 or
10 micrograms/mL, for 24 hours, and their ability to release interleukin-1,
interleukin-6, and tumor necrosis factor was assessed by bioassay. RESULTS:
Chronic low-dose ETX with 0 microgram of ETX media added produced early (at
1 hour) in vivo activation of PM luminal diameter interleukin-1 release,
which was comparable to that seen in mice subjected to CLP. However, unlike
PM luminal diameter taken from CLP mice, PM luminal diameters from mice
implanted with the ETX minipump at 1 or 24 hours showed no marked decline
in their ability to respond to ETX (10 micrograms). Comparable changes were
seen for interleukin-6 and tumor necrosis factor release. CONCLUSIONS:
Bacterial component(s) other than ETX per se induces the sustained
dysfunction in PM luminal diameter capacity to produce proinflammatory
cytokines during sepsis and/or peritonitis. Thus, agents directed against
ETX alone may not be adequate in the treatment of polymicrobial sepsis.
