title: P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice.
abstract: Inflammation contributes to liver injury in acetaminophen (APAP) hepatotoxicity in mice and is triggered by stimulation of immune cells. The purinergic receptor P2X7 is upstream of the nod-like receptor family, pryin domain containing-3 (NLRP3) inflammasome in immune cells and is activated by ATP and NAD that serve as damage-associated molecular patterns. APAP hepatotoxicity was assessed in mice genetically deficient in P2X7, the key inflammatory receptor for nucleotides (P2X7-/-), and in wild-type mice. P2X7-/- mice had significantly decreased APAP-induced liver necrosis. In addition, APAP-poisoned mice were treated with the specific P2X7 antagonist A438079 or etheno-NAD, a competitive antagonist of NAD. Pre- or posttreatment with A438079 significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury in wild-type but not P2X7-/- mice. Pretreatment with etheno-NAD also significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury. In addition, APAP toxicity in mice lacking the plasma membrane ecto-NTPDase CD39 (CD39-/-) that metabolizes ATP was examined in parallel with the use of soluble apyrase to deplete extracellular ATP in wild-type mice. CD39-/- mice had increased APAP-induced hemorrhage and mortality, whereas apyrase also decreased APAP-induced mortality. Kupffer cells were treated with extracellular ATP to assess P2X7-dependent inflammasome activation. P2X7 was required for ATP-stimulated IL-1β release. In conclusion, P2X7 and exposure to the ligands ATP and NAD are required for manifestations of APAP-induced hepatotoxicity.
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA.
authors.forename: Rafaz
authors.initials: R
authors.lastname: Hoque
authors.forename: Muhammed Adnan
authors.initials: MA
authors.lastname: Sohail
authors.forename: Steven
authors.initials: S
authors.lastname: Salhanick
authors.forename: Ahsan F
authors.initials: AF
authors.lastname: Malik
authors.forename: Ayaz
authors.initials: A
authors.lastname: Ghani
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Wajahat Z
authors.initials: WZ
authors.lastname: Mehal
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D058633:Antipyretics / Q000009:adverse effects*; D001081:Apyrase / Q000378:metabolism; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000031:analogs & derivatives / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D015703:Antigens, CD; D058633:Antipyretics; D058847:Inflammasomes; D053583:Interleukin-1beta; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; D009243:NAD; D000082:Acetaminophen; D001081:Apyrase; C067869:CD39 antigen