Wehrle Chase J, Panconesi Rebecca, Satish Sangeeta, Maspero Marianna, Jiao Chunbao, Sun Keyue, Karakaya Omer, Allkushi Erlind, Modaresi Esfeh Jamak, Whitsett Linganna Maureen, Ma Wen Wee, Fujiki Masato, Hashimoto Koji, Miller Charles, Kwon David C H, Aucejo Federico, Schlegel Andrea
Transplantation Center, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Cancers (Basel). 2024 Aug 7;16(16):2789. doi: 10.3390/cancers16162789.
Liver transplantation is known to generate significant inflammation in the entire organ based on the metabolic profile and the tissue's ability to recover from the ischemia-reperfusion injury (IRI). This cascade contributes to post-transplant complications, affecting both the synthetic liver function (immediate) and the scar development in the biliary tree. The new occurrence of biliary strictures, and the recurrence of malignant and benign liver diseases, such as cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC), are direct consequences linked to this inflammation. The accumulation of toxic metabolites, such as succinate, causes undirected electron flows, triggering the releases of reactive oxygen species (ROS) from a severely dysfunctional mitochondrial complex 1. This initiates the inflammatory IRI cascade, with subsequent ischemic biliary stricturing, and the upregulation of pro-tumorigenic signaling. Such inflammation is both local and systemic, promoting an immunocompromised status that can lead to the recurrence of underlying liver disease, both malignant and benign in nature. The traditional treatment for CCA was resection, when possible, followed by cytotoxic chemotherapy. Liver transplant oncology is increasingly recognized as a potentially curative approach for patients with intrahepatic (iCCA) and perihilar (pCCA) cholangiocarcinoma. The link between IRI and disease recurrence is increasingly recognized in transplant oncology for hepatocellular carcinoma. However, smaller numbers have prevented similar analyses for CCA. The mechanistic link may be even more critical in this disease, as IRI causes the most profound damage to the intrahepatic bile ducts. This article reviews the underlying mechanisms associated with biliary inflammation and biliary pathology after liver transplantation. One main focus is on the link between transplant-related IRI-associated inflammation and the recurrence of cholangiocarcinoma and benign liver diseases of the biliary tree. Risk factors and protective strategies are highlighted.
众所周知，基于代谢特征以及组织从缺血再灌注损伤（IRI）中恢复的能力，肝移植会在整个器官中引发显著的炎症反应。这种级联反应会导致移植后并发症，影响肝脏的合成功能（直接影响）以及胆管树中的瘢痕形成。胆管狭窄的新出现，以及恶性和良性肝脏疾病（如胆管癌（CCA）和原发性硬化性胆管炎（PSC））的复发，都是与这种炎症相关的直接后果。有毒代谢产物（如琥珀酸）的积累会导致无定向电子流，触发严重功能失调的线粒体复合物1释放活性氧（ROS）。这启动了炎症性IRI级联反应，随后出现缺血性胆管狭窄，并上调促肿瘤信号。这种炎症反应既是局部的，也是全身性的，会促进免疫功能低下状态，进而导致潜在的肝脏疾病（无论恶性还是良性）复发。CCA的传统治疗方法是在可能的情况下进行切除，然后进行细胞毒性化疗。肝移植肿瘤学越来越被认为是治疗肝内（iCCA）和肝门周围（pCCA）胆管癌患者的一种潜在治愈方法。在肝细胞癌的移植肿瘤学中，IRI与疾病复发之间的联系越来越受到认可。然而，由于病例数量较少，尚未对CCA进行类似的分析。在这种疾病中，机制联系可能更为关键，因为IRI对肝内胆管造成的损害最为严重。本文综述了肝移植后与胆管炎症和胆管病理相关的潜在机制。一个主要重点是移植相关的IRI相关炎症与胆管癌和胆管树良性肝脏疾病复发之间的联系。文中强调了风险因素和保护策略。
