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

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 t issue injury and death. Bile duct-ligated (BDL) cirrhotic and control rats were challenged with lipopolysaccharide (LPS). Sensitivity to LPS was marke dly enhanced in the BDL group, and was associated with increased liver inju ry and mortality. There was a 5-fold constitutive activation of nuclear fac tor kappa B (NF kappa B) in the liver of BDL rat controls (P < .001), and t his was activated further, but to a similar extent, in the liver of both sh am and BDL rats after injection of LPS. Plasma tumor necrosis factor alpha (TNF-alpha) increased more markedly in the BDL cirrhotic rats (2,463 +/- 69 7 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 con trols at baseline, and increased further after LPS (P < .05), but did not d iffer from sham controls at 6 hours. Plasma F-2-isoprostanes increased 6-fo ld in the cirrhotic rats and 2-fold in the controls (P < .01) indicative of lipid peroxidation. Esterified F-2-isoprostanes in the liver increased 2- to 3-fold at 1 hour in control and BDL rats, but returned to baseline level s by 3 hours. Esterified F-2-isoprostanes in the kidney increased by 2-fold in the BDL rats after LPS administration, bur remained unchanged in sham c ontrols. We conclude that there is a marked increase in sensitivity to LPS in BDL cirrhotic rats. This is associated with an enhanced TNF-alpha respon se and increased lipid peroxidation. These may be directly and causally rel ated to mortality.