Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity.
Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity.
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DOI：
10.3390/ijms21175998
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发表时间：
2020-08-20
影响因子：
5.6
通讯作者：
Schmelzle M
中科院分区：
文献类型：
--
作者：
Feldbrügge L;Splith K;Kämmerer I;Richter S;Riddermann A;Ortiz Galindo SA;Krenzien F;Müller T;Csizmadia E;Pratschke J;Robson SC;Schmelzle M
外核苷酸酶三磷酸二磷酸水解酶-2（NTPDase 2）是一种在肝门静脉成纤维细胞上表达的胞外酶，通过调节细胞外ATP和ADP的局部浓度来调节P2受体信号传导。NTPD酶2在肝纤维化中具有保护特性，并可能影响胆管上皮更新。在这里，我们研究了NTPDase 2在急性肝损伤中的作用，使用对乙酰氨基酚（APAP）中毒的实验模型与NTPDase 2的整体缺失的小鼠。在野生型（WT）和NTPD酶2缺陷型（Entpd 2 null）小鼠中给予对乙酰氨基酚引起急性肝毒性。通过组织学和血清谷丙转氨酶（ALT）比较肝损伤程度。通过qPCR确定炎症、再生和纤维化的标志物。我们发现，Entpd 2的表达显着上调后，对乙酰氨基酚诱导的肝毒性。与WT相比，Entpd 2缺失小鼠显示出显著更多的坏死和更高的血清ALT。在Entpd 2敲除小鼠中，IL-6和PDGF-B的肝脏表达更高。我们的数据表明门静脉成纤维细胞表达的NTPDase 2在急性坏死性肝损伤中的诱导和保护作用。进一步的研究应该调查这些嘌呤能通路在肝门静脉周围和肝窦生物学的相关性，因为这种理解的进展可能提供可能的治疗靶点。
Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets.
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影响因子：
4.9
作者：
Liñán-Rico A;Turco F;Ochoa-Cortes F;Harzman A;Needleman BJ;Arsenescu R;Abdel-Rasoul M;Fadda P;Grants I;Whitaker E;Cuomo R;Christofi FL
通讯作者：
Christofi FL
影响因子：
4.8
作者：
Jhandier, MN;Kruglov, EA;Dranoff, JA
通讯作者：
Dranoff, JA
影响因子：
5.2
作者：
Gampe, Kristine;Stefani, Jennifer;Hammer, Klaus;Brendel, Peter;Poetzsch, Alexandra;Enikolopov, Grigori;Enjyoji, Keiichi;Acker-Palmer, Amparo;Robson, Simon C.;Zimmermann, Herbert
通讯作者：
Zimmermann, Herbert
影响因子：
13.5
作者：
Gao, Rachel Y.;Wang, Meng;Ju, Cynthia
通讯作者：
Ju, Cynthia
DOI：
10.1073/pnas.1309468110
发表时间：
2013-09-03
影响因子：
11.1
作者：
Vandenbeuch, Aurelie;Anderson, Catherine B.;Kinnamon, Sue C.
通讯作者：
Kinnamon, Sue C.