P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice.
Am J Physiol Gastrointest Liver Physiol
; 302(10): G1171-9, 2012 May 15.
Article
em En
| MEDLINE
| ID: mdl-22383490
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-1ß release. In conclusion, P2X7 and exposure to the ligands ATP and NAD are required for manifestations of APAP-induced hepatotoxicity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença Hepática Induzida por Substâncias e Drogas
/
Receptores Purinérgicos P2X7
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Antipiréticos
/
Acetaminofen
Limite:
Animals
Idioma:
En
Revista:
Am J Physiol Gastrointest Liver Physiol
Assunto da revista:
FISIOLOGIA
/
GASTROENTEROLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos