Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Division of Cardiothoracic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
J Hepatol. 2023 Dec;79(6):1396-1407. doi: 10.1016/j.jhep.2023.08.010. Epub 2023 Aug 21.
BACKGROUND & AIMS: Biliary atresia (BA) is an obstructive cholangiopathy that initially affects the extrahepatic bile ducts (EHBDs) of neonates. The etiology is uncertain, but evidence points to a prenatal cause. Fetal tissues have increased levels of hyaluronic acid (HA), which plays an integral role in fetal wound healing. The objective of this study was to determine whether a program of fetal wound healing is part of the response to fetal EHBD injury.
Mouse, rat, sheep, and human EHBD samples were studied at different developmental time points. Models included a fetal sheep model of prenatal hypoxia, human BA EHBD remnants and liver samples taken at the time of the Kasai procedure, EHBDs isolated from neonatal rats and mice, and spheroids and other models generated from primary neonatal mouse cholangiocytes.
A wide layer of high molecular weight HA encircling the lumen was characteristic of the normal perinatal but not adult EHBD. This layer, which was surrounded by collagen, expanded in injured ducts in parallel with extensive peribiliary gland hyperplasia, increased mucus production and elevated serum bilirubin levels. BA EHBD remnants similarly showed increased HA centered around ductular structures compared with age-appropriate controls. High molecular weight HA typical of the fetal/neonatal ducts caused increased cholangiocyte spheroid growth, whereas low molecular weight HA induced abnormal epithelial morphology; low molecular weight HA caused matrix swelling in a bile duct-on-a-chip device.
The fetal/neonatal EHBD, including in human EHBD remnants from Kasai surgeries, demonstrated an injury response with prolonged high levels of HA typical of fetal wound healing. The expanded peri-luminal HA layer may swell and lead to elevated bilirubin levels and obstruction of the EHBD.
Biliary atresia is a pediatric cholangiopathy associated with high morbidity and mortality rates; although multiple etiologies have been proposed, the fetal response to bile duct damage is largely unknown. This study explores the fetal pathogenesis after extrahepatic bile duct damage, thereby opening a completely new avenue to study therapeutic targets in the context of biliary atresia.
胆道闭锁（BA）是一种阻塞性胆管病，最初影响新生儿的肝外胆管（EHBD）。病因尚不确定，但有证据表明其病因发生在产前。胎儿组织中透明质酸（HA）水平升高，HA 在胎儿伤口愈合中发挥着重要作用。本研究旨在确定胎儿伤口愈合程序是否是对胎儿 EHBD 损伤反应的一部分。
研究了不同发育时间点的小鼠、大鼠、绵羊和人 EHBD 样本。模型包括产前缺氧的胎羊模型、Kasai 手术时取的人 BA EHBD 残余物和肝脏样本、从新生大鼠和小鼠分离的 EHBD 以及由原代新生小鼠胆管细胞生成的球体和其他模型。
正常围生期而非成年 EHBD 的特征是围绕管腔的高分子量 HA 宽层。该层被胶原包围，在受损的胆管中与广泛的胆管旁腺增生、增加的黏液产生和升高的血清胆红素水平平行扩张。与年龄匹配的对照相比，BA EHBD 残余物中同样显示出围绕胆管结构的 HA 增加。类似于胎儿/新生儿胆管的高分子量 HA 导致胆管细胞球体生长增加，而低分子量 HA 导致上皮形态异常；低分子量 HA 导致胆管芯片设备中的基质肿胀。
包括 Kasai 手术后人类 EHBD 残余物在内的胎儿/新生儿 EHBD 表现出具有延长的、类似于胎儿伤口愈合的高水平 HA 的损伤反应。扩大的管腔周围 HA 层可能会肿胀，导致胆红素水平升高和 EHBD 阻塞。
胆道闭锁是一种与高发病率和死亡率相关的儿科胆管病；尽管提出了多种病因，但 EHBD 损伤后的胎儿反应在很大程度上尚不清楚。本研究探讨了肝外胆管损伤后的胎儿发病机制，从而为胆道闭锁背景下的治疗靶点研究开辟了全新途径。
