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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice
American Journal of Physiology - Gastrointestinal and Liver Physiology, Volume 302, No. 10, Year 2012
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Description
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. © 2012 the American Physiological Society.
Authors & Co-Authors
Ghani, Ayaz
United States, New Haven
Yale University
Robson, Simon Christopher
United States, West Haven
Va Connecticut Healthcare System
Mehal, Wajahat Zafar
United States, New Haven
Yale University
United States, West Haven
Va Connecticut Healthcare System
Statistics
Citations: 111
Authors: 3
Affiliations: 3
Identifiers
Doi:
10.1152/ajpgi.00352.2011
ISSN:
15221547
Research Areas
Violence And Injury