修回日期: 2026-06-07
接受日期: 2026-07-02
在线出版日期: 2026-07-28
肝细胞缺血缺氧在肝硬化的发生发展中起关键作用, 且二者形成恶性循环. 缺氧条件下, 肝细胞内缺氧诱导因子(hypoxia inducible factor, HIF)-1α稳定积累, 并通过活性氧、内质网应激等非HIF依赖途径协同参与肝细胞损伤. 肝细胞通过旁分泌CXC型趋化因子配体12、转化生长因子-β及血管内皮生长因子等信号分子, 激活肝星状细胞、诱导肝窦毛细血管化并加重门脉高压. 缺血缺氧还可诱导肝细胞衰老, 衰老细胞通过旁分泌促进炎症反应, 再生障碍与纤维化失衡最终加速肝硬化失代偿. 本文围绕上述机制进行系统综述, 并针对抗血管新生、保护肝窦内皮、抑制肝细胞衰老及靶向HIF通路等方向提出研究展望, 以期为肝硬化防治提供新思路.
核心提要: 肝细胞缺血缺氧在肝硬化的发生发展中起关键作用. 缺氧条件下, 肝细胞内信号通路的激活, 参与门脉高压形成, 并诱导肝细胞衰老及肝窦内皮细胞表型改变, 进而加速肝硬化进展. 本文以文献综述形式, 围绕肝细胞缺血缺氧对肝细胞损伤、血管新生、肝窦毛细血管化及肝细胞衰老的影响等方面进行综述, 以期为肝硬化的发生发展机制研究提供参考.
引文著录: 唐鑫, 蔡伟浩, 毛卫, 熊隆信. 肝细胞缺血缺氧在肝硬化进展中的作用及机制. 世界华人消化杂志 2026; 34(7): 541-547
Revised: June 7, 2026
Accepted: July 2, 2026
Published online: July 28, 2026
Hepatocellular ischemia and hypoxia are pivotal drivers of both the initiation and progression of liver cirrhosis, establishing a self-perpetuating vicious cycle. Within the hypoxic microenvironment, hypoxia-inducible factor-1α (HIF-1α) accumulates in hepatocytes, and together with non-HIF-dependent mechanisms such as reactive oxygen species overproduction and endoplasmic reticulum stress, this accumulation exacerbates hepatocellular injury. In response, hepatocytes secrete a range of signaling mediators, including C-X-C motif chemokine ligand 12, transforming growth factor-β, and vascular endothelial growth factor. These factors further activate hepatic stellate cells, promote sinusoidal capillarization, and worsen portal hypertension. Additionally, ischemia and hypoxia induce hepatocellular senescence. Senescent hepatocytes release pro-inflammatory cytokines in a paracrine manner, and the resultant imbalance between defective liver regeneration and relentless fibrosis ultimately drives the progression toward decompensated cirrhosis. Herein, we systematically review the aforementioned pathological mechanisms and outline prospective research strategies focusing on angiogenesis modulation, sinusoidal endothelial cell protection, hepatocellular senescence, and the HIF signaling pathway. This work aims to offer novel perspectives for the prevention and clinical management of liver cirrhosis.
- Citation: Tang X, Cai WH, Mao W, Xiong LX. Hepatocyte ischemia and hypoxia in liver cirrhosis progression: Pathophysiological roles and molecular mechanisms. Shijie Huaren Xiaohua Zazhi 2026; 34(7): 541-547
- URL: https://www.wjgnet.com/1009-3079/full/v34/i7/541.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i7.541
核心提要: 肝细胞缺血缺氧在肝硬化的发生发展中起关键作用. 缺氧条件下, 肝细胞内信号通路的激活, 参与门脉高压形成, 并诱导肝细胞衰老及肝窦内皮细胞表型改变, 进而加速肝硬化进展. 本文以文献综述形式, 围绕肝细胞缺血缺氧对肝细胞损伤、血管新生、肝窦毛细血管化及肝细胞衰老的影响等方面进行综述, 以期为肝硬化的发生发展机制研究提供参考.
肝硬化是由病毒性肝炎、酒精性肝病、非酒精性脂肪性肝病等多种病因导致的肝脏出现弥漫性纤维化伴假小叶形成, 最终肝脏质地变硬、肝功能逐渐衰退的终末期肝病阶段. 持续的肝细胞损伤是肝硬化的始动环节, 肝内微循环障碍所引发的缺血缺氧状态既是肝硬化的病理改变结果, 也是加速疾病进展的关键因素[1]. 在肝硬化的发生发展过程中, 肝窦毛细血管化及门脉高压等一系列病理变化的形成使肝细胞长期处于缺氧微环境中[2]. 肝脏的缺血缺氧状态进一步诱导肝细胞发生死亡、功能衰退及代谢障碍, 并通过细胞间的信号交流加剧肝脏炎症与纤维化, 促成肝小叶结构破坏及假小叶的形成, 加速肝纤维化的进程[3]. 目前, 肝细胞中缺氧诱导因子(hypoxia inducible factor, HIF)信号的精细调控机制尚不明确, HIF通路与非HIF依赖途径的相互影响、缺氧诱导肝细胞衰老的具体分子机制等仍有待阐明. 因此阐明肝细胞在缺血缺氧下的应答机制及其对肝硬化进程的影响, 对于寻找新的治疗靶点、延缓肝硬化进展具有重要意义. 本文将对相关研究进展进行系统综述.
在肝硬化进程中, 伴随肝组织结构的破坏及门脉高压的形成, 这些改变直接影响肝内微循环, 是肝细胞缺血缺氧的重要解剖基础[4]. 肝窦毛细血管化导致肝窦内皮细胞的窗孔消失并形成连续性基底膜, 进而阻碍氧供和营养物质的交换. 毛细血管化的肝窦内皮细胞还可通过释放血管细胞黏附分子-1和转化生长因子-β(transforming growth factor-β, TGF-β)等激活肝星状细胞(hepatic stellate cell, HSC), 增加细胞外基质的沉积, 诱导假小叶形成[5,6]. 增生的纤维间隔压迫血管, 门脉高压的形成加剧肝内异常动静脉分流, 使肝窦有效灌注减少, 局部缺氧状态显著加重[7]. 这些改变共同致使肝细胞氧供减少, 成为驱动后续肝细胞损伤及肝纤维化进展的关键环节.
肝细胞感知缺氧的核心通路是HIF通路. 正常状态下, 肝细胞内HIF-α亚基的脯氨酸残基被脯氨酰羟化酶羟基化, 进而被希佩尔林道蛋白识别并降解, 因此蛋白水平极低. 缺氧时脯氨酰羟化酶的活性受到抑制, HIF-1α稳定积累并转位入核与HIF-1β形成二聚体, 进而结合靶基因启动子区的缺氧反应元件, 启动转录应答[8,9]. 常氧时天冬酰胺羟化酶(factor inhibiting HIF1, FIH)催化HIF-α C端转录激活结构域的天冬酰胺羟基化, 阻断其与转录共激活因子E1A结合蛋白p300/CREB结合蛋白的结合而抑制转录活性; 缺氧时FIH活性受抑, 该抑制解除, 进一步增强HIF的转录活性[10]. 缺氧条件下肝细胞中活化的HIF-1α通过将潜伏型TGF-β转化为活性型TGF-β, 进而上调趋化因子CXC型趋化因子配体12(C-X-C motif chemokine ligand 12, CXCL12)的表达, 促进HSC活化和细胞外基质的沉积[11,12]. 肝细胞特异性HIF-1α敲除小鼠模型为上述机制提供了关键证据, Mesarwi等[13]在间歇性缺氧模型中发现, 与野生型对照相比, 肝细胞特异性HIF-1α敲除小鼠肝脏中胶原含量及胶原交联相关基因赖氨酰氧化酶样1基因的表达均显著降低, 直接证实肝细胞HIF-1α在缺氧诱导的肝纤维化中不可或缺.
肝硬化微环境中肝细胞缺血缺氧的发生源于肝内血流重构所导致的氧供不足, 而肝细胞通过HIF通路感知缺氧并启动下游靶基因的转录应答, 为其后续的肝细胞损伤效应及促肝硬化作用奠定了基础. 缺氧还可通过活性氧(reactive oxygen species, ROS)、内质网应激等非HIF依赖途径影响肝细胞功能, 具体机制将在下文中阐述.
当肝细胞处于缺氧状态时, 线粒体的氧化磷酸化功能因氧供不足而受阻, 三磷酸腺苷(adenosine triphosphate, ATP)合成随之大幅下降, 直接导致钠钾泵功能障碍, 细胞内水钠潴留出现细胞水肿, 最终使细胞陷入整体能量危机[14]. 与此同时, 线粒体氧化呼吸链功能发生障碍, 电子泄漏生成大量ROS, 从而引发氧化应激爆发[15]. ROS具有较强的氧化能力, 可直接攻击线粒体膜、内质网膜以及质膜中富含的多不饱和脂肪酸, 从而启动脂质过氧化式反应, 使细胞器功能进一步受损[16]. 尽管肝细胞自身具备一定的抗氧化防御能力, 但当肝脏长时间处于缺血缺氧状态时, 细胞内的谷胱甘肽等抗氧化物质被过度消耗, 氧化与抗氧化之间的平衡随之被打破, 细胞最终走向不可逆损伤[17]. 能量代谢障碍与氧化应激之间相互促进, 二者共同构成一个恶性循环. 该循环是诱发肝细胞后续死亡及功能衰退的关键因素.
肝细胞处于缺氧环境下时, 其死亡方式不再是传统意义上的坏死, 而是呈现为多种程序性死亡模式的异常激活. 凋亡是一种经典的程序性细胞死亡方式, 当肝细胞处于缺氧环境时, 线粒体的膜电位会随之下降, 促使细胞色素c从线粒体释放到细胞浆中, 进而激活内源性含半胱氨酸的天冬氨酸蛋白水解酶通路, 导致肝细胞凋亡[18-20]. 但肝细胞本身高表达B细胞淋巴瘤-2、B细胞淋巴瘤X长链蛋白等凋亡抑制蛋白, 且缺氧状态下细胞可通过激活自噬、内质网应激适应性反应等机制启动部分促生存信号通路, 因此单纯由缺氧诱导的肝细胞凋亡程度可能较为有限[21-23]. 值得注意的是, 轻度内质网应激可发挥适应性保护作用, 而持续重度内质网应激则可通过蛋白激酶R样内质网激酶/真核翻译起始因子2α/活化转录因子4通路诱导肝细胞凋亡[23]. 近年来备受关注的铁死亡是一种铁依赖性的非凋亡性死亡, 其死亡特征为脂质过氧化物大量积聚以及谷胱甘肽过氧化物酶4(glutathione peroxidase 4, GPX4)的活性丧失[24]. 在缺氧环境下的肝细胞中, 铁死亡表现尤为明显. 缺氧诱导线粒体发生功能障碍, 进而产生大量ROS[25]. 与此同时, 细胞内GPX4的表达以及谷胱甘肽的合成均受到抑制, 导致细胞膜中的多不饱和脂肪酸更易遭受过氧化攻击, 而长链脂酰辅酶A合成酶4在缺氧的肝细胞中表达的升高, 为铁死亡的发生提供了反应底物[26-28]. Cai等[26]在动物模型中进一步证实, 缺氧可显著降低肝组织GPX4蛋白水平并升高脂质过氧化产物丙二醛, 而铁死亡抑制剂铁抑素-1可减轻脂质积累并改善肝功能. 此外, 坏死性凋亡也是缺氧环境下肝细胞发生的一种重要程序性死亡. 长期缺氧可不依赖经典的肿瘤坏死因子α-肿瘤坏死因子受体1信号通路, 通过调节受体相互作用蛋白激酶1的脯氨酸羟基化, 直接触发坏死性凋亡[29]. 最近研究显示[30], 缺氧还可通过Z-DNA结合蛋白1/受体相互作用蛋白激酶3信号轴诱导原代肝细胞发生坏死性凋亡. 自噬与铁死亡之间存在复杂的相互作用, 但二者在肝硬化中的具体关系及调控机制尚不明确, 仍有待进一步研究. 细胞发生不同形式的死亡时, 会释放出损伤相关分子模式(damageassociated molecular patterns, DAMPs), 这些分子是诱发肝脏炎症反应和纤维化的重要因素.
在缺氧状态下存活下来的肝细胞, 其核心功能发生全面衰退. 在合成功能方面, 白蛋白的合成能力显著降低, 这既反映出蛋白质合成能力已广泛受损, 也使血浆胶体渗透压下降, 间接推动腹水的形成[31]. 在代谢解毒方面, 缺氧引起的肝细胞损伤会导致血氨清除能力下降. 高氨血症不仅是肝性脑病的病理基础, 还可直接诱导肝细胞的死亡[32]. 同时转运功能同样受到显著影响, 缺氧可显著下调肝细胞中钠离子-牛磺胆酸共转运多肽、胆盐输出泵以及多药耐药相关蛋白2等负责胆汁酸摄取的关键转运蛋白的mRNA表达, 该变化直接导致胆汁酸排泄减少, 引起胆汁淤积性肝功能障碍[33]. 在药物代谢方面, 缺氧对肝细胞造成的影响同样不可忽视, 缺氧诱导的HIF-1α稳定表达可下调细胞色素P450家族1亚家族A成员2、细胞色素P450家族2亚家族B成员6和细胞色素P450家族3亚家族A成员4等关键代谢酶的mRNA水平, 严重削弱肝脏的解毒能力, 使内源性和外源性毒物在体内蓄积[34]. 上述功能衰退虽非肝细胞特异性改变, 但在肝硬化缺氧微环境中持续存在, 从多方面加速肝硬化进程.
在缺氧微环境的作用下, 肝细胞除出现能量缺乏与功能减退等表现外, 还呈现出表型转化的特征, 以主动的方式参与肝硬化的进展. 肝细胞在缺氧微环境下HIF-1α的表达持续升高, 可促进潜伏型TGF-β1的活化, 诱导E-钙黏蛋白上皮标志物表达下调, 同时促使α-平滑肌动蛋白(alphasmooth muscle actin, α-SMA)、成纤维细胞特异性蛋白-1等间充质标志物表达上调, 上述变化共同表明, 肝细胞发生上皮-间质转化, 直接参与细胞外基质的沉积[35].
上述缺血缺氧状态下肝细胞出现的HIF通路激活、死亡模式改变、代谢功能减退以及分泌表型重塑等一系列改变, 并非彼此孤立, 而是通过细胞间信号传递与相互作用, 将缺氧信号转化为推动肝硬化进程的直接驱动力. 研究证实[36-38], 缺氧的肝细胞可通过旁分泌TGF-β1、释放DAMPs、诱导血管内皮生长因子(vascular endothelial growth factor, VEGF)表达以及调控外泌体等多种方式, 共同加速肝硬化的发生与发展.
缺氧条件下, 肝细胞可通过多种旁分泌途径参与HSC的激活, 从而推动肝纤维化的进展. CXC型趋化因子配体12-CXC型趋化因子受体4信号轴在肝纤维化中的促纤维化作用已被多项研究证实[39,40]. 肝细胞在缺氧状态下通过HIF-1α和TGF-β通路显著上调分泌性趋化因子CXCL12的表达, 该因子与HSC表面的CXC型趋化因子受体4结合, 激活HSC并促进α-SMA和I型胶原的表达增加, 进而增加细胞外基质的沉积[11,41], 推动肝硬化的进程. CXCL12还可通过Rho激酶通路进一步诱导HSC收缩, 增加肝内血流阻力, 参与肝硬化门脉高压的形成[42]. TGF-β1虽被公认为最强的促纤维化因子, 在缺氧肝细胞中表达亦升高, 但肝细胞来源的TGF-β1是否以旁分泌方式通过经典的转化生长因子-β1/信号转导蛋白Smad通路激活HSC, 目前尚缺乏直接实验证据[43,44].
缺血缺氧时, 受损的肝细胞会释放多种DAMPs. 除高迁移率族蛋白B1(high mobility group box 1, HMGB1)外, 肝细胞内功能障碍的线粒体亦会释放线粒体DNA、ATP等分子. 这些线粒体来源的DAMPs同样能激活HSC, 推动肝纤维化[45]. 实验证实, 肝细胞是缺血缺氧后HMGB1的主要来源. 在1% O2浓度的单纯缺氧条件下即可诱导原代肝细胞发生Toll样受体4(toll-like receptor 4, TLR4)依赖的ROS产生, 进而促进HMGB1释放[46]. 肝细胞特异性TLR4敲除小鼠在缺血再灌注后循环HMGB1水平显著降低, 进一步支持了肝细胞作为HMGB1主要来源的结论[47]. 近年研究发现[48], 在缺氧/复氧条件下, 肝细胞内HMGB1的乳酸化修饰是其分泌的重要调控机制. 释放至胞外的HMGB1与库普弗细胞表面的TLR4结合, 通过髓样分化因子88依赖的核因子κB通路诱导库普弗细胞向促炎表型极化, 进而分泌肿瘤坏死因子-α、白细胞介素-1β(interleukin1β, IL-1β)等炎症因子[49,50]. 有研究还发现[51], 在缺氧/复氧条件下, 肝细胞内核苷酸结合寡聚化结构域样受体家族含pyrin结构域蛋白3炎症小体的激活, 可促进IL-1β和白细胞介素-18的释放, 进一步放大炎症信号. 这些炎症因子的释放会加重邻近肝细胞的损伤, 同时也能激活HSC, 促使其转化为肌成纤维细胞, 大量沉积细胞外基质, 破坏肝小叶的正常结构并形成假小叶, 从而加速肝硬化进展.
在肝硬化进程中, 缺氧微环境是驱动肝内血管病变和门脉高压的关键因素. 缺氧状态下肝细胞内HIF-1α表达升高, 进而促进大量VEGF的分泌, Gao等[52]在肝硬化患者及动物模型中证实, VEGF及血管内皮生长因子受体2(vascular endothelial growth factor receptor 2, VEGFR2)表达较正常对照组显著增加, 且与肝内血管生成密切相关. 这些VEGF与肝窦内皮细胞(liver sinusoidal endothelial cell, LSEC)表面的VEGFR2结合, 促进内皮细胞增殖、迁移和管腔形成. 同时VEGF的持续刺激还可诱导LSEC发生表型改变, 表现为窗孔消失和连续性基底膜形成, 即肝窦毛细血管化[53]. 这不仅阻碍氧气与营养物质在肝细胞与血液之间的交换, 还进一步加重肝细胞的缺氧状态. 在肝硬化持续存在的缺氧环境下, VEGF诱导的新生血管往往结构扭曲、通透性高且缺乏正常细胞覆盖. 这种病理性血管增生不仅无法有效改善肝内灌注, 反而增加血流阻力并加剧血管渗漏. 此外, 肝细胞分泌的内皮素-1等缩血管物质, 也可作用于LSEC和HSC, 引起肝窦收缩, 进一步升高肝内阻力[54,55]. 这一系列血管结构与功能的紊乱, 使得门脉高压与肝细胞缺血缺氧相互促进, 形成缺氧与血流异常互为因果的正反馈环. 随着缺氧程度的不断加重, 最终加速肝硬化向失代偿期进展.
缺氧状态下, 肝细胞内肝细胞生长因子/细胞间质上皮转化因子受体增殖信号通路受到抑制, 导致肝细胞增殖能力下降[56]. 同时, 缺氧可诱导肝细胞内缺氧诱导因子-2α稳定表达, 进而抑制过氧化物酶体增殖物激活受体α/过氧化物酶体增殖物激活受体γ共激活因子1α信号通路介导的脂质氧化通路, 引起能量供应不足和持续性脂肪变性, 阻碍肝细胞增殖[57]. 上述结果说明, 缺氧可直接抑制肝细胞增殖信号和能量代谢, 造成再生障碍.
除直接抑制增殖信号外, 缺氧还可能通过诱导肝细胞衰老间接损害再生能力. 在多种细胞类型中, 缺氧条件下细胞内HIF-1α的积累可上调细胞周期依赖性激酶抑制剂2A(cyclin-dependent kinase inhibitor 2A, p16)、肿瘤蛋白p53、核纤层蛋白B1及细胞周期蛋白D1等衰老标志物的水平[58]. 虽然肝细胞中该通路尚缺乏直接验证, 但已有研究表明[59,60]其衰老与p16、lamin B1等标志物密切相关, 且氧化应激、酒精等均可触发肝细胞发生应激诱导的早衰. 衰老的肝细胞进一步分泌白细胞介素-6、白细胞介素-8等衰老相关分泌表型, 通过旁分泌方式作用于邻近细胞, 进而促进炎症反应[61].
由于功能健全的肝细胞数量减少且增殖能力下降, 肝脏受损后无法有效再生. 肝硬化病理条件下, 残存肝细胞代偿性增生形成再生结节, 但这些结节往往缺乏正常肝小叶结构, 中央静脉缺失且血供紊乱, 进一步加重局部缺氧和纤维化. 肝细胞再生障碍与纤维组织代偿性增生的失衡, 是假小叶形成和肝小叶结构破坏的重要病理基础.
缺血缺氧是肝硬化进展的重要微环境因素, 可影响肝细胞损伤、血管新生、肝窦毛细血管化及肝细胞衰老等多个环节, 与肝硬化形成恶性循环. 缺氧条件下肝细胞内HIF稳定积累, 参与门脉高压形成, 后者进一步加重肝细胞缺血缺氧. 缺血缺氧还可诱导肝细胞衰老, 衰老的肝细胞增殖能力下降, 同时通过旁分泌促进炎症反应. 肝细胞再生障碍与纤维组织增生的失衡, 最终加速肝硬化向失代偿期进展. 目前, 肝细胞特异性缺氧信号的具体调控机制尚不明确, 其在肝细胞衰老和肝窦内皮细胞表型调控中的具体作用仍有待进一步研究. 针对肝窦毛细血管化, 联合抗VEGF与保护肝窦内皮功能的策略值得深入评估. 缺氧诱导的肝细胞衰老及其旁分泌效应可能成为干预肝硬化进展的新靶点. 此外, 不同缺氧阶段下HIF信号的动态变化及其与非HIF依赖通路的相互影响, 均有待进一步阐明.
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学科分类: 胃肠病学和肝病学
手稿来源地: 江西省
同行评议报告学术质量分类
A级 (优秀): 0
B级 (非常好): B, B
C级 (良好): C
D级 (一般): 0
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科学编辑: 刘继红 制作编辑:张砚梁