Characterization of an Inducible Alcoholic Liver Fibrosis Model for Hepatocellular Carcinoma Investigation in a Transgenic Porcine Tumorigenic Platform
Characterization of an Inducible Alcoholic Liver Fibrosis Model for Hepatocellular Carcinoma Investigation in a Transgenic Porcine Tumorigenic Platform
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DOI：
10.1016/j.jvir.2018.03.007
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发表时间：
2018-08-01
影响因子：
2.9
通讯作者：
Schachtschneider, Kyle M.
中科院分区：
文献类型：
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作者：
Gaba, Ron C.;Mendoza-Elias, Nasya;Schachtschneider, Kyle M.
目的：本研究使用 Oncopig 癌症模型 (OCM) 在能够发展为肝细胞癌的猪模型中开发酒精诱导的纤维化。 材料和方法：通过肝动脉输注 0.75 mL/kg 乙醇乙碘油 (1:3 v/v)，在 8 周龄 Oncopig (n = 10) 中诱导肝损伤。在诱导后 8 周通过组织学分析评估初始 Oncopig 队列 (n = 5) 的可行性，并将 METAVIR 结果与年龄和性别匹配的健康对照 (n = 5) 进行比较。然后在第二个 OCM 队列 (n = 5) 中诱导肝损伤进行时程研究，通过每两周一次体检、实验室分析和肝活检进行诱导后疾病监测，直至诱导后 20 周。 结果：在队列 1 中，诱导后 8 周肝脏组织学分析显示中位 METAVIR F3（范围，F3-F4）纤维化，A2（范围，A2-A3） 炎症和 15.3%（范围，5.0%-22.9%）纤维化。与健康对照相比，METAVIR 和炎症评分普遍升高（F0-F1，P = 0.0013；A0-A1，P = 0.0013；中位纤维化百分比 8.7%，范围 5.8%-12.1%，P = 0.064）。在队列 2 中，组织学分析显示中位 METAVIR F3（范围，F2-F3）的纤维化严重程度达到峰值。然而，缺乏持续的酒精暴露导致肝脏恢复，诱导后 20 周时中位 METAVIR F2（范围，F1-F2）纤维化。没有观察到表明肝脏失代偿的行为或生化异常。 结论：这项研究成功验证了在 OCM 中 8 周内发展 METAVIR F3-F4 纤维化的方案，支持其作为纤维化肝脏背景中肝细胞癌模型的潜力。需要进一步研究以确定是否需要反复酒精性肝损伤来建立不可逆的 METAVIR F4 级猪肝硬化模型。
PURPOSE: This study used the Oncopig Cancer Model (OCM) to develop alcohol-induced fibrosis in a porcine model capable of developing hepatocellular carcinoma.MATERIALS AND METHODS: Liver injury was induced in 8-week-old Oncopigs (n = 10) via hepatic transarterial infusion of 0.75 mL/kg ethanol-ethiodized oil (1:3 v/v). Feasibility was assessed in an initial Oncopig cohort (n = 5) by histologic analysis at 8 weeks after induction, and METAVIR results were compared to age- and sex-matched healthy controls (n = 5). Liver injury was then induced in a second OCM cohort (n = 5) for a time-course study, with post-induction disease surveillance via biweekly physical exam, lab analysis, and liver biopsies until 20 weeks after induction.RESULTS: In Cohort 1, 8-week post-induction liver histologic analysis revealed median METAVIR F3 (range, F3-F4) fibrosis, A2 (range, A2-A3) inflammation, and 15.3% (range, 5.0%-22.9%) fibrosis. METAVIR and inflammation scores were generally elevated compared to healthy controls (F0-F1, P = 0.0013; A0-A1, P = .0013; median percent fibrosis 8.7%, range, 5.8%-12.1%, P = .064). In Cohort 2, histologic analysis revealed peak fibrosis severity of median METAVIR F3 (range, F2-F3). However, lack of persistent alcohol exposure resulted in liver recovery, with median METAVIR F2 (range, F1-F2) fibrosis at 20 weeks after induction. No behavioral or biochemical abnormalities were observed to indicate liver decompensation.CONCLUSIONS: This study successfully validated a protocol to develop METAVIR F3-F4 fibrosis within 8 weeks in the OCM, supporting its potential to serve as a model for hepatocellular carcinoma in a fibrotic liver background. Further investigation is required to determine if repeated alcohol liver injury is required to develop an irreversible METAVIR grade F4 porcine cirrhosis model.