Role of the Bcl-2 family and TRAIL signaling in paracetamol-induced necrosis in liver cells

肝脏在营养物质的储存和代谢中起着重要的作用。然而，由于其广泛的血管化，它也是各种病原体相关免疫病变和不良药物副作用的常见目标。扑热息痛（Paracetamol， APAP）是一种应用广泛的镇痛和解热药物。虽然在治疗剂量下被认为是安全的，但意外或故意过量服用APAP可能导致严重的肝损伤甚至死亡。apap诱导的肝细胞死亡和相关肝衰竭的潜在机制尚不完全清楚，尽管坏死而不是凋亡似乎是介导肝损伤的原因。我们之前的研究表明，Bcl-2家族成员在apap诱导的肝损伤中起关键作用，这一过程被TRAIL受体信号放大。最近，我们发现在APAP治疗后，肝细胞中诱导了促凋亡的BH3-only蛋白Bim、Noxa和Puma。因此，本项目的具体目的是了解APAP促进这些Bcl-2同源物表达的机制，它们在APAP诱导的肝损伤中各自的作用，Bcl-2家族成员如何与这种坏死形式的细胞死亡相互作用或调节，以及TRAIL信号如何调节APAP诱导的肝细胞死亡。本研究获得的结果将揭示Bcl-2同源物在这种形式的药物性肝损伤中的作用，特别是在坏死细胞死亡中，以及TRAIL信号如何与这些过程相互作用。最后但并非最不重要的是，这项研究可能有助于确定新的潜在靶点，开发新的药物治疗APAP中毒和相关的肝损害。

The liver has important functions in the storage and metabolism of nutrients. Due to its extensive vascularization it is, however, also frequent target of various pathogen-associated immunopathologies and adverse drug side-effects. Paracetamol (APAP) is a widely used drug with analgesic and anti-pyretic properties. Although considered safe at therapeutic doses, accidental or intentional APAP overdose may cause severe liver damage and even death. The underlying mechanisms of APAP-induced hepatocyte death and associated liver failure are incompletely understood, although necrosis rather than apoptosis appears to be responsible for mediating liver damage. We have previously shown that Bcl-2 family members critically contribute to APAP-induced liver damage, in a process, which amplified by TRAIL receptor signaling. More recently we have seen that the pro-apoptotic BH3-only proteins Bim, Noxa and Puma are induced in hepatocytes upon APAP treatment. The specific aims of this project are therefore to understand the mechanisms by which APAP promotes the expression of these Bcl-2 homologs, what their respective role is in APAP-induced liver damage, how Bcl-2 family members interact with or regulate this necrotic form of cell death, and finally how TRAIL signaling regulates APAP-induced hepatocyte death. The results obtained in this study will shed new light into the role of Bcl-2 homologs in this form of drug-induced liver damage in general and in necrotic cell death in particular, and how TRAIL signaling interacts with these processes. Last but not least this study may help to identify novel potential targets to develop new drugs for the treatment of APAP intoxication and associated liver damage.