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 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.


METHODS
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.
D000818:Animals; D004731:Endotoxins / Q000097:blood / Q000502:physiology*; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008026:Ligation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010533:Peritoneal Lavage; D011677:Punctures; D018805:Sepsis / Q000276:immunology*; D014115:Toxemia / Q000276:immunology
D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6