The Coagulation System Contributes to Synergistic Liver Injury from Exposure to Monocrotaline and Bacterial Lipopolysaccharide

Coexposure to a noninjurious dose of bacterial lipopolysaccha-ride (LPS; 7.4 106 EU/kg) and a nontoxic dose of the food-borne toxin monocrotaline (MCT; 100 mg/kg) leads to synergistic hepa-totoxicity in Sprague-Dawley rats. Inflammatory factors, such as Kupffer cells (KCs), tumor necrosis factor- (TNF)-, and neu-trophils (polymorphonuclear leukocytes; PMNs), are critical to the pathogenesis. Inasmuch as activation of the coagulation system and sinusoidal endothelial cell (SEC) injury precede hepatic pa-renchymal cell (HPC) injury, and since fibrin deposition occurs within liver lesions, the coagulation system might be a critical component of injury. In this study, this hypothesis is tested, and the interdependence of the coagulation system and inflammatory factors is explored. Administration of the anticoagulants heparin or warfarin to MCT/LPS-cotreated animals attenuated HPC and SEC injury. Morphometric analysis revealed that anticoagulant treatment significantly reduced the area of centrilobular and mid-zonal lesions. Heparin treatment also reduced fibrin deposition in these regions. Furthermore, anticoagulant treatment decreased hepatic PMN accumulation but did not affect plasma TNF- concentration. Neither KC inactivation nor TNF- depletion pre-vented activation of the coagulation system. PMN depletion, how-ever, prevented coagulation system activation, suggesting that PMNs are needed for this response. These results provide evidence that the coagulation system and its interplay with PMNs are important in the pathogenesis of MCT/LPS-induced liver injury. Key Words: liver; inflammation; lipopolysaccharide; monocro-taline; coagulation system; fibrin deposition; heparin; warfarin

CYP2E1 potentiation of LPS and TNFα-induced hepatotoxicity by mechanisms involving enhanced oxidative and nitrosative stress, activation of MAP kinases, and mitochondrial dysfunction

The mechanisms by which alcohol causes cell injury are not clear. A major mechanism that is the focus of considerable research is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a role in how alcohol induces oxidative stress. Considerable attention has been given to alcohol-elevated production of lipopolysaccharide (LPS) and TNFα and to alcohol induction of CYP2E1. These two pathways are not exclusive of each other, however, associations and interactions between them, especially in vivo, have not been extensively evaluated. We have shown that increased oxidative stress from induction of CYP2E1 in vivo sensitizes hepatocytes to LPS and TNF toxicity and that oxidants, such as peroxynitrite, activation of p38 and JNK MAP kinases, inactivation of NF-kB protective pathways and mitochondrial dysfunction are downstream mediators of this CYP2E1-LPS/TNF potentiated hepatotoxicity. This review will summarize studies showing potentiated interactions between these two risk factors in promoting liver injury and the mechanisms involved