Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity.
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.
['Feldbrügge|Linda|L|', 'Splith|Katrin|K|', 'Kämmerer|Ines|I|', 'Richter|Sandra|S|', 'Riddermann|Anna|A|', 'Ortiz Galindo|Santiago Andres|SA|', 'Krenzien|Felix|F|0000-0003-0593-9917', 'Müller|Tobias|T|', 'Csizmadia|Eva|E|', 'Pratschke|Johann|J|', 'Robson|Simon C|SC|', 'Schmelzle|Moritz|M|']
D000082:Acetaminophen D000251:Adenosine Triphosphatases D000410:Alanine Transaminase D000469:Alkaline Phosphatase D000818:Animals D056486:Chemical and Drug Induced Liver Injury D005347:Fibroblasts D015971:Gene Expression Regulation, Enzymologic D015850:Interleukin-6 D008099:Liver D008115:Liver Regeneration D008222:Lymphokines D008297:Male D008810:Mice, Inbred C57BL D008817:Mice, Mutant Strains D009336:Necrosis D010982:Platelet-Derived Growth Factor D014409:Tumor Necrosis Factor-alpha
NTPDase2 Entpd2 APAP hepatotoxicity purinergic signaling