Intrahepatic microcirculatory disorder, parenchymal hypoxia and NOX4 upregulation result in zonal differences in hepatocyte apoptosis following lipopolysaccharide- and D-galactosamine-induced acute liver failure in rats.
Intrahepatic microcirculatory disorder, parenchymal hypoxia and NOX4 upregulation result in zonal differences in hepatocyte apoptosis following lipopolysaccharide- and D-galactosamine-induced acute liver failure in rats.
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DOI：
10.3892/ijmm.2013.1573
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发表时间：
2014-02
影响因子：
5.4
通讯作者：
Takayanagi R
中科院分区：
文献类型：
--
作者：
Tanaka M;Tanaka K;Masaki Y;Miyazaki M;Kato M;Kotoh K;Enjoji M;Nakamuta M;Takayanagi R
尽管急性肝衰竭（ALF）的发病机制尚未完全阐明，但研究表明，肝内巨噬细胞激活通过肝内微循环障碍以及随之而来的实质细胞死亡，在ALF的发病机制中起着重要作用。利用活体显微镜在动物模型中已证实存在肝内微循环障碍；然而，该方法的局限性包括无法同时评估血流及周围的病理变化。因此，在本研究中，我们设计了一种新方法，即使用异硫氰酸四甲基罗丹明（TRITC） - 葡聚糖给药来对肝脏微循环进行病理评估。此外，我们旨在阐明肝内微循环障碍与活化巨噬细胞相关的进展机制。通过给予脂多糖和D - 半乳糖胺诱导Wistar大鼠发生ALF。观察ALF大鼠肝脏3区（中心周围区）的肝内微循环和微循环障碍。免疫组织化学检查结合TRITC - 葡聚糖图像显示，巨噬细胞主要分布在2区（中间区），而裂解的半胱天冬酶 - 3阳性肝细胞、乏氧诱导因子1 - α和吡莫硝唑在3区大量存在。我们还发现4 - 羟基 - 2 - 壬烯醛和烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）4阳性细胞主要位于3区实质。3区的大多数凋亡肝细胞与NOX4共定位。我们的研究结果表明，3区的凋亡细胞是肝内微循环障碍诱导的缺氧状况所致，而非由活化的巨噬细胞诱导。3区氧化应激水平的升高可能促进了肝细胞凋亡的进展。
Although the mechanisms responsible for acute liver failure (ALF) have not yet been fully elucidated, studies have indicated that intrahepatic macrophage activation plays an important role in the pathogenesis of ALF through intrahepatic microcirculatory disorder and consequent parenchymal cell death. Intrahepatic microcirculatory disorder has been demonstrated in animal models using intravital microscopy; however, the limitations of this method include simultaneously evaluating blood flow and the surrounding pathological changes. Therefore, in this study, we devised a novel method involving tetramethylrhodamine isothiocyanate (TRITC)-dextran administration for the pathological assessment of hepatic microcirculation. In addition, we aimed to elucidate the mechanisms through which intrahepatic microcirculatory disorder progresses with relation to activated macrophages. ALF was induced in Wistar rats by exposure to lipopolysaccharide and D-galactosamine. Intrahepatic microcirculation and microcirculatory disorder in zone 3 (pericentral zone) of the livers of rats with ALF was observed. Immunohistochemical examinations in conjunction with TRITC-dextran images revealed that the macrophages were mainly distributed in zone 2 (intermediate zone), while cleaved caspase-3-positive hepatocytes, pimonidazole and hypoxia-inducible factor 1-α were abundant in zone 3. We also found that 4-hydroxy-2-nonenal and nicotinamide adenine dinucleotide phosphate oxidase (NOX)4-positive cells were predominantly located in the zone 3 parenchyma. The majority of apoptotic hepatocytes in zone 3 were co-localized with NOX4. Our results revealed that the apoptotic cells in zone 3 were a result of hypoxic conditions induced by intrahepatic microcirculatory disorder, and were not induced by activated macrophages. The increased levels of oxidative stress in zone 3 may contribute to the progression of hepatocyte apoptosis.
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DOI：
10.1124/jpet.107.122069
发表时间：
2007-08
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Deng X;Luyendyk JP;Zou W;Lu J;Malle E;Ganey PE;Roth RA
通讯作者：
Roth RA
影响因子：
8
作者：
Cifuentes-Pagano, Eugenia;Csanyi, Gabor;Pagano, Patrick J.
通讯作者：
Pagano, Patrick J.
影响因子：
3.3
作者：
Diebold I;Petry A;Hess J;Görlach A
通讯作者：
Görlach A
影响因子：
7.3
作者：
Borbely, Gabor;Szabadkai, Istvan;Keri, Gyoergy
通讯作者：
Keri, Gyoergy
影响因子：
29.4
作者：
De Minicis, Samuele;Bataller, Ramon;Brenner, David A.
通讯作者：
Brenner, David A.