taurochenodeoxycholic-acid and Liver-Failure

Ischemic-type biliary lesions (ITBL) are the most troublesome biliary complication after liver transplantation (LT) from non-heart-beating donors (NHBD) and frequently result in death or re-transplantation. In transplantation process, warm ischemia (WI) in the donor, cold ischemia and reperfusion injury in the recipient altogether inducing ischemia-reperfusion injury (IRI) is strongly associated with ITBL. This is a cascading injury process, involving in a complex series of inter-connecting events causing variety of cells activation and damage associated with the massive release of inflammatory cytokines and generation of reactive oxygen species (ROS). These damaged cells such as sinusoidal endothelial cells (SECs), Kupffer cells (KCs), hepatocytes and biliary epithelial cells (BECs), coupled with immunological injury and bile salt toxicity altogether contribute to ITBL in NHBD LT. Developed therapeutic strategies to attenuate IRI are essential to improve outcome after LT. Among them, single pharmaceutical interventions blocking a specific pathway of IRI in rodent models play an absolutely dominant role, and show a beneficial effect in some given controlled experiments. But this will likely prove ineffective in complex clinical setting in which more risk parameters are involved. Therefore, we intend to design a multidrug cocktail approach to block different pathways on more than one stage (WI, cold ischemia and reperfusion) of the process of IRI-induced ITBL simultaneously. This multidrug cocktail will include six drugs containing streptokinase, epoprostenol, thiazolidinediones (TZDs), N-Acetylcysteine (NAC), hemin and tauroursodeoxycholic acid (TUDC). These drugs show protective effects by targeting the different key events of IRI, such as anti-inflammatory, anti-fibrosis, anti-oxidation, anti-apoptosis and reduced bile salt toxicity. Ideally, the compounds, dosage, and method of application of drugs included in cocktail should not be definitive. We can consider removing or adding some drugs to the proposed cocktail based on further research. But given the multitude of different combinations, it is extremely difficult to determent which combination is the optimization design. Nevertheless, regardless of the difficulty, our multidrug cocktail approach designed to block different mechanisms on more than one stage of IRI simultaneously may represent a future preventive and therapeutic avenue for ITBL.

Topics: Acetylcysteine; Animals; Biliary Tract Diseases; Drug Therapy, Combination; Epithelial Cells; Epoprostenol; Female; Hemin; Hepatocytes; Humans; Inflammation; Ischemia; Kupffer Cells; Liver; Liver Failure; Liver Transplantation; Models, Theoretical; Organ Preservation; Reactive Oxygen Species; Reoperation; Reperfusion Injury; Streptokinase; Swine; Taurochenodeoxycholic Acid; Thiazolidinediones; Tissue Donors; Warm Ischemia

It has been demonstrated that plasma from patients with fulminant hepatic failure (FHF) interferes extensively with cellular function. We placed primary human and primary porcine hepatocytes in a polyurethane foam (PUF)/spheroid culture system and compared the metabolic functions in the plasma of patients with FHF in a 24-h stationary culture to those in a monolayer culture. The PUF/spheroid culture system using primary human and primary porcine hepatocytes significantly decreased ammonia content during 28-day culture. Fisher's ratio significantly increased at culture days 3 and 7. Tauroursodeoxycholic acid significantly increased and glycochenodeoxycholic acid and taurochenodeoxycholic acid decreased in the FHF patients' plasma at culture day 3. During at least a 24-h culture in the FHF patients' plasma, metabolic functions of primary human and primary porcine hepatocytes were almost identical. The present results indicate that the PUF/spheroid culture system using primary human or primary porcine hepatocytes demonstrated more advantageous metabolic functions in the plasma from patients with FHF than the monolayer culture.

Topics: Ammonia; Animals; Bile Acids and Salts; Cell Culture Techniques; Cells, Cultured; Glycochenodeoxycholic Acid; Hepatocytes; Humans; Liver Failure; Polyurethanes; Spheroids, Cellular; Swine; Taurochenodeoxycholic Acid; Time Factors