Ramm G A, Nair V G, Bridle K R, Shepherd R W, Crawford D H
The Hepatic Fibrosis Group, Clinical Sciences Unit, The Queensland Institute of Medical Research, Brisbane, Australia.
Am J Pathol. 1998 Aug;153(2):527-35. doi: 10.1016/S0002-9440(10)65595-2.
Extrahepatic biliary atresia is a severe neonatal liver disease resulting from a sclerosing cholangiopathy of unknown etiology. Although biliary obstruction may be surgically corrected by a "Kasai" hepatoportoenterostomy, most patients still develop progressive hepatic fibrosis, although the source of increased collagen deposition is unclear. This study examined the role of hepatic stellate cells (HSCs) and assessed the source of transforming growth factor-beta (TGF-beta) production in hepatic fibrogenesis in patients with biliary atresia. Liver biopsies from 18 biliary atresia patients (including 5 pre- and post-Kasai) were subjected to immunohistochemistry for alpha-smooth muscle actin and in situ hybridization for either procollagen alpha1 (I) mRNA or TGF-beta1 mRNA. Sections were also subjected to immunohistochemistry for active TGF-beta1 protein. The role of Kupffer cells in TGF-beta1 production was assessed by immunohistochemistry for CD68. Procollagen alpha1 (I) mRNA was colocalized to alpha-smooth muscle actin-positive HSCs within the region of increased collagen protein deposition in fibrotic septa and surrounding hyperplastic bile ducts. The number of activated HSCs was decreased in only one post-Kasai biopsy. TGF-beta1 mRNA expression was demonstrated in bile duct epithelial cells and activated HSCs and in hepatocytes in close proximity to fibrotic septa. Active TGF-beta1 protein was demonstrated in bile duct epithelial cells and activated HSCs. This study provides evidence that activated HSCs are responsible for increased collagen production in patients with biliary atresia and therefore play a definitive role in the fibrogenic process. We have also shown that bile duct epithelial cells, HSCs, and hepatocytes are all involved in the production of the profibrogenic cytokine, TGF-beta1.
肝外胆管闭锁是一种严重的新生儿肝脏疾病，由病因不明的硬化性胆管病引起。尽管胆管梗阻可通过“Kasai”肝门肠吻合术进行手术矫正，但大多数患者仍会出现进行性肝纤维化，尽管胶原沉积增加的来源尚不清楚。本研究探讨了肝星状细胞（HSC）的作用，并评估了胆管闭锁患者肝纤维化过程中转化生长因子-β（TGF-β）产生的来源。对18例胆管闭锁患者（包括5例Kasai手术前后的患者）的肝活检组织进行α-平滑肌肌动蛋白免疫组织化学检测，以及I型前胶原α1（procollagen alpha1 (I)）mRNA或TGF-β1 mRNA原位杂交检测。切片还进行了活性TGF-β1蛋白免疫组织化学检测。通过CD68免疫组织化学检测评估库普弗细胞在TGF-β1产生中的作用。在纤维化间隔和周围增生胆管中胶原蛋白沉积增加的区域内，I型前胶原α1 mRNA与α-平滑肌肌动蛋白阳性的HSC共定位。仅在1例Kasai手术后的活检组织中，活化HSC的数量减少。在胆管上皮细胞、活化的HSC以及紧邻纤维化间隔的肝细胞中均检测到TGF-β1 mRNA表达。在胆管上皮细胞和活化的HSC中检测到活性TGF-β1蛋白。本研究提供了证据，表明活化的HSC是胆管闭锁患者胶原产生增加的原因，因此在纤维化过程中起决定性作用。我们还表明，胆管上皮细胞、HSC和肝细胞均参与了促纤维化细胞因子TGF-β1的产生。
