To dissect the in vivo responses to lipopolysaccharide compared with nonlipopolysaccharide structures of whole meningococci.
Comparative experimental study.
University hospital with an animal intensive care unit and laboratory.
Twenty-four anesthetized healthy Norwegian landrace pigs of 30 kg (± 2.5 kg) grouped into two test groups and one control group.
Exponentially increasing numbers of Neisseria meningitidis H44/76 (NmLPS+) or a knockout mutant of H44/76 completely lacking lipopolysaccharide (NmLPS−) were infused intravenously to the pigs.
Measurements and Main Results:
Physiological and hematologic parameters were continuously recorded and biochemical analyses were performed in batch after completion. Systemic vascular resistance, cardiac index and lactate changed significantly more in the NmLPS+ than in the NmLPS− group (p < .05). Mean pulmonary artery pressure increased early in the NmLPS+ and late in the NmLPS− group, but finally reached equally high values. Capillary leakage (fluid requirement, plasma albumin loss, organ wet/dry ratio) was more prominent in the NmLPS+ group (p < .05). Leukocytes were depleted in a highly lipopolysaccharide-dependent manner (p < .001). Thrombin-antithrombin complexes and plasminogen activator inhibitor-1 increased 2.5 to five times more in the NmLPS+ group (p < .05). Maximum cytokine concentrations in plasma were markedly higher in the NmLPS+ group (p < .05): tumor necrosis factor-α (40 times), interleukin-1β (40 times), interleukin-6 (13 times), and interleukin-10 (four times). Interleukin-12 increased only in the NmLPS+ group.
This large animal model, which simulates human disease well, confirms the potency of lipopolysaccharide but provides clear evidence that nonlipopolysaccharide molecules induce cardiovascular and hematologic changes quite similar to those caused by lipopolysaccharide. In general, 10- to 20-fold higher doses of the lipopolysaccharide-deficient mutant were required to induce the same degree of pathophysiological changes. Endotoxic activity of Gram-negative bacteria should no longer be attributed solely to the activity of lipopolysaccharide.