Kupffer cell blockade improves liver microcirculation in endotoxemia following experimental bile duct ligation

Introduction: Previously we demonstrated that attenuation of Kupffer cell (KC) function with gadolinium chloride (GdCl3) decreases endotoxin-induced morbidity in experimental bile duct ligation (BDL). Endotoxemia causes inflammatory reaction in the liver, and KC inhibition reduces neutrophil activation in this condition. Herein we compared the microcirculatory consequences of BDL with or without acute endotoxemia, and examined the effects of GdCl3 in these disorders.

Methods: The liver microcirculation was visualized using fluorescence intravital videomicroscopy (IVM). Capillary perfusion rate, neutrophil-endothelial interactions and KC activity (latex microbead deposition/acinus) were assessed off-line. Microcirculatory variables were examined in control group, lipopolysaccharide-treated group (LPS, 1mg/kg iv, 2 hr before IVM) and BDL (3 days before IVM) and after combined BDL+LPS challenge. The same experiments were repeated in four parallel groups which were pre-treated with GdCl3 (1mg/100g iv). Serum Il-6 and TNF-α levels, tissue myeloperoxidase activity was measured, the extent of histological damage was evaluated in liver biopsies.

Results: KC activity was approx. 3 times higher after BDL and in endotoxemia than in the control group and approx. 5 times increase was observed after BDL+LPS. The ratio of perfused capillaries in the liver acini did not change significantly in the LPS group, but significantly decreased in BDL and BDL+LPS groups. In BDL the number of sticking leukocytes was similar to that observed after sham operation but significantly increased in response to LPS or BDL+LPS. KC blockade did not influence the perfusion failure caused by BDL+LPS, but significantly ameliorated the inflammatory leukocyte reactions.

Conclusions: BDL causes severe perfusion failure with a moderate leukocyte reaction in the liver. LPS with BDL induces higher degree of KC activation and microcirculatory failure than LPS alone. A second hit with LPS re-enhances KC activation, thus causing perfusion failure and liver inflammation in obstructive jaundice.