Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic rat

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Abstract
Sepsis is a common complication of cirrhosis with a high mortality. In this study, we have investigated some of the pathways that may be involved in tissue injury and death. Bile duct-ligated (BDL) cirrhotic and control rats were challenged with lipopolysaccharide (LPS). Sensitivity to LPS was markedly enhanced in the BDL group, and was associated with increased liver injury and mortality. There was a 5-fold constitutive activation of nuclear factor κ B (NFκB) in the liver of BDL rat controls (P < .001), and this was activated further, but to a similar extent, in the liver of both sham and BDL rats after injection of LPS. Plasma tumor necrosis factor α (TNF-α) increased more markedly in the BDL cirrhotic rats (2,463 ± 697 pg/mL in BDL rats versus 401 ± 160 pg/mL in the controls at 3 hours; P < .01). Plasma nitrite/nitrate concentrations were increased in the BDL controls at baseline, and increased further after LPS (P < .05), but did not differ from sham controls at 6 hours. Plasma F2-isoprostanes increased 6-fold in the cirrhotic rats and 2-fold in the controls (P < .01) indicative of lipid peroxidation. Esterified F2-isoprostanes in the liver increased 2- to 3-fold at 1 hour in control and BDL rats, but returned to baseline levels by 3 hours. Esterified F2-isoprostanes in the kidney increased by 2-fold in the BDL rats after LPS administration, but remained unchanged in sham controls. We conclude that there is a marked increase in sensitivity to LPS in BDL cirrhotic rats. This is associated with an enhanced TNF-α response and increased lipid peroxidation. These may be directly and causally related to mortality.

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