Does Prolonged Biliary Obstructive Jaundice Sensitize the Liver to Endotoxemia?

Abstract

Biliary obstructive jaundice (OJ) is an important clinical consideration concerning high bacteremic risk. Hepatocyte apoptosis is one of the causes of cholestatic liver injury. The aim of the current study was to examine the precise pathway and time course of hepatocyte apoptosis during OJ with LPS administration and to determine if OJ sensitizes the liver to endotoxemia. Male C57BL/6 mice were subjected to bile duct ligation and division and were administered with LPS at 3 (OJ3) or 14 (OJ14) days after surgery. Fas ligand expression, poly (adenosine diphosphate-ribose) polymerase p85 fragment immunohistochemistry, activation of caspases 3, 8, and 9, serum alanine aminotransferase levels, and hepatic adenosine triphosphate (ATP) contents were examined. Survival after LPS administration in male C57BL/6 or gld/gld (Fas ligand-deficient) mice was determined. The expression of Fas ligand increased during OJ. After LPS administration, the expression of cleaved caspases 3 and 8 increased in Sham3, Sham14, OJ3, and OJ14 mice, and it significantly increased in OJ14 compared with other mice. Poly (adenosine diphosphate-ribose) polymerase p85 immunohistochemistry showed significant hepatocyte apoptosis after LPS administration in OJ14 mice relative to OJ3. In OJ14 with LPS administration, ATP contents significantly decreased and alanine aminotransferase levels increased. Hepatocyte apoptosis was decreased in gld/gld OJ14 mice compared with C57BL/6 OJ14. All C57BL/6 OJ14 mice with LPS died, but survival in gld/gld OJ14 significantly ameliorated. In prolonged OJ with LPS administration, hepatocyte apoptosis depending on Fas ligand expression significantly increased in association with a decrease in ATP contents, thus resulting in liver necrapoptosis.

Increased liver elasticity in patients with biliary obstruction

“…OJ causes hyperlipidemia and this might have affected the data in our study [32]. Also, we did not have enough data on serum lipids in our patients.…”

Treatment with dimethyl fumarate ameliorates liver ischemia/reperfusion injury

“…Our results showed that DMF enhanced eNOS protein expression, suggesting that DMF pretreatment may protect endothelial function from I/RI. Furthermore, cellular apoptosis consumes large amounts of nicotinamide adenine dinucleotide (NAD + ), and the process to resynthesize NAD + decreases the level of cellular ATP[33]. Our data showed that the ATP content was increased in the DMF group compared to that in the CTL group, suggesting that DMF has an anti-apoptotic effect.…”

Hepatocyte apoptosis is enhanced after ischemia/reperfusion in the steatotic liver

“…(28,29) Our previous studies have demonstrated that cellular apoptosis consumes a large amount of nicotinamide adenine dinucleotide (NAD+), and to resynthesize NAD+, resulting in a decrease in ATP levels. (30) Combination with hepatocyte apoptosis and ATP depletion changes the cellular response to secondary oncotic necrosis. (31) These findings suggest that hepatocyte apoptosis in conjunction with a decrease in ATP levels causes secondary oncotic necrosis, leading to significant liver injury.…”