George, as is evident from the conclusions presented below, the significance of the role that endotoxins play, in many maladies, is still a topic of considerable debate:
Ann Surg 1997 May;225(5):530-41; discussion 541-3
Is circulating endotoxin the trigger for the systemic inflammatory response syndrome seen after injury?
Kelly JL, O'Sullivan C, O'Riordain M, O'Riordain D, Lyons A, Doherty J, Mannick JA, Rodrick ML
Department of Surgery, Harvard Medical School-Brigham and Women's Hospital, Boston, Massachusetts, USA.
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-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6
(IL-6). The correlation of increased plasma LPS with TNF-alpha production was studied as was the association of increased plasma LPS and increased
TNF-alpha 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-alpha, IL-1 beta, and IL-6. Expression of the messenger RNAs for IL-1 beta and TNF-alpha also was measured. The relation of
increased TNF-alpha 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-alpha 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-alpha, IL-1 beta, and IL-6. Increased TNF-alpha production was not correlated with elevated plasma LPS in the same patients.
Neither increased plasma LPS nor increased TNF-alpha 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-alpha and IL-1 beta 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-alpha 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.
PMID: 9193181, UI: 97336430
ncbi.nlm.nih.gov
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