Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.
Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.
复制标题
低剂量对乙酰氨基酚诱导人肝细胞和小鼠肝脏中细胞细胞紧密连接的早期破坏。
DOI：
10.1038/srep37541
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发表时间：
2017-01-30
影响因子：
4.6
通讯作者：
Nelson LJ
中科院分区：
文献类型：
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作者：
Gamal W;Treskes P;Samuel K;Sullivan GJ;Siller R;Srsen V;Morgan K;Bryans A;Kozlowska A;Koulovasilopoulos A;Underwood I;Smith S;Del-Pozo J;Moss S;Thompson AI;Henderson NC;Hayes PC;Plevris JN;Bagnaninchi PO;Nelson LJ
细胞-细胞紧密连接（TJ）粘附功能障碍是各种疾病发病机制的主要特征。肝脏TJ通过界定功能性胆管结构，形成血胆屏障来保持细胞极性。在对乙酰氨基酚肝毒性中，影响组织凝聚力和极性的机制仍不清楚。在这里，我们证明，对乙酰氨基酚，即使在低剂量下，破坏TJ和细胞-基质粘附的完整性，在人肝HepaRG细胞系和原代肝细胞中具有肝损伤的细胞应激指标。在小鼠肝脏中，在人类等效（治疗）剂量下，细胞间肝TJ相关ZO-1蛋白表达的剂量依赖性丧失明显，伴有肝损伤的进行性临床体征。时间，剂量依赖性和特定的破坏TJ相关的ZO-1和细胞内-F-肌动蛋白，与肝脏超微结构的调制。实时阻抗生物传感验证了在体外早期，剂量依赖性定量减少TJ和细胞基质粘附。然而，用NAPQI、对乙酰氨基酚的反应性代谢物或PKCα激活剂和TJ破坏剂佛波醇-12-肉豆蔻酸酯-13-乙酸酯治疗，同样降低了TJ完整性，这可能涉及氧化应激和TJ不稳定中的PKC途径。这些发现与对乙酰氨基酚肝毒性的临床表现有关，并可能为未来的机制研究提供信息，以确定对乙酰氨基酚诱导的肝去极化中可能改变的特定分子靶点和途径。
Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization.
DOI：
10.1083/jcb.109.2.697
发表时间：
1989-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jaken S;Leach K;Klauck T
通讯作者：
Klauck T