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Is Circulating Endotoxin the Trigger for the Systemic Inflammatory Response Syndrome Seen After Injury?

Kelly, John L. M.B., B.Ch.; O'Sullivan, Christopher M.B., B.Ch.; O'Riordain, Michael M.B., B.Ch.; O'Riordain, Diarmuid M.B., B.Ch.; Lyons, Ann M.B., B.Ch.; Doherty, Jane B.S.; Mannick, John A. M.D.; Rodrick, Mary L. Ph.D.

Scientific Papers
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Objective Patients with severe traumatic or burn injury and a mouse model of burn injury were studied early after injury to determine the relation of plasma endotoxin (lipopolysaccharide [LPS]) to the production of proinflammatory cytokines and subsequent resistance to infection.

Summary Background Data Elevated levels of plasma LPS have been reported in patients after serious injury. It has been suggested that circulating LPS may be a trigger for increased proinflammatory cytokine production and may play a role in the septic syndromes seen in a substantial portion of such patients. Yet, despite multiple reports of leakage of LPS from the gut and bacterial translocation after injury in animal models, there is little direct evidence linking circulating LPS with production of inflammatory mediators.

Methods The authors studied serial samples of peripheral blood from 10 patients with 25% to 50% surface area burns and 8 trauma patients (Injury Severity Score, 25-57). Patients were compared with 18 healthy volunteers. The study was focused on the first 10 days after injury before the onset of sepsis or the systemic inflammatory response syndrome. Plasma samples were assayed for LPS, and adherent cells from the blood were studied for basal and LPS-stimulated production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). The correlation of increased plasma LPS with TNF-α production was studied as was the association of increased plasma LPS and increased TNF-α production with subsequent septic complications. We also studied a mouse model of 25% burn injury. Burn mice were compared with sham burn control subjects. Plasma samples were assayed at serial intervals for LPS, and adherent cells from the spleens were studied for basal- and LPS-stimulated production of TNF-α, IL-1β, and IL-6. Expression of the messenger RNAs for IL-1β and TNF-α also was measured. The relation of increased TNF-α production with mortality from a septic challenge, cecal ligation and puncture (CLP), was determined. Finally, the effect of administration of LPS to normal mice on subsequent mortality after CLP and on TNF-α production was studied.

Results Elevated plasma LPS (>1 pg/mL) was seen in 11 of the 18 patients within 10 days of injury and in no normal control subjects. In this period, patients as compared with control subjects showed increased stimulated production of TNF-α, IL-1β, and IL-6. Increased TNF-α production was not correlated with elevated plasma LPS in the same patients. Neither increased plasma LPS nor increased TNF-α production early after injury was correlated with subsequent development of systemic inflammatory response syndrome or sepsis in the patients. Burn mice, as compared with sham burn control subjects, showed elevated plasma LPS levels chiefly in the first 3 days after injury. Increased stimulated production of proinflammatory cytokines by adherent splenocytes from the burn mice also was seen at multiple intervals after injury and did not correlate with mortality from CLP. Increased production of TNF-α and IL-1β was associated with increased expression of messenger RNAs for these cytokines. Finally, two doses of 1 ng LPS administered 24 hours apart to normal mice had no effect on mortality from CLP performed 7 days later nor on the production of TNF-α at the time of CLP.

Conclusions These findings call into question the idea that circulating LPS is the trigger for increased proinflammatory cytokine production, systemic inflammatory response syndrome, and septic complications in injured patients.

From the Department of Surgery, Harvard Medical School-Brigham and Women's Hospital, Boston, Massachusetts

Address reprint requests to John A. Mannick, M.D., Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Accepted for publication December 13, 1996.

Presented at the 108th Annual Meeting of the Southern Surgical Association, December 1-4, 1996, Palm Beach, Florida.

Supported in part by NIH grant #GM35633-12, the Julian and Eunice Cohen Surgery Research Fund, the David Brook Fund for Vascular Research, and a grant from the North Atlantic Treaty Organization.

© Lippincott-Raven Publishers.