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ALTERED RESPONSIVENESS TO EXTRACELLULAR ATP ENHANCES ACETAMINOPHEN HEPATOTOXICITY
Sterile inflammation
Acetaminophen
Remote injury
Cell death
Immune system
Inflammation
Purinergic signaling
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Affilliation
Abstract
Background: Adenosine triphosphate (ATP) is secreted from hepatocytes under physiological conditions and plays
an important role in liver biology through the activation of P2 receptors. Conversely, higher extracellular ATP
concentrations, as observed during necrosis, trigger inflammatory responses that contribute to the progression of
liver injury. Impaired calcium (Ca2+) homeostasis is a hallmark of acetaminophen (APAP)-induced hepatotoxicity,
and since ATP induces mobilization of the intracellular Ca2+ stocks, we evaluated if the release of ATP during
APAP-induced necrosis could directly contribute to hepatocyte death.
Results: APAP overdose resulted in liver necrosis, massive neutrophil infiltration and large non-perfused areas, as
well as remote lung inflammation. In the liver, these effects were significantly abrogated after ATP metabolism by
apyrase or P2X receptors blockage, but none of the treatments prevented remote lung inflammation, suggesting a
confined local contribution of purinergic signaling into liver environment. In vitro, APAP administration to primary
mouse hepatocytes and also HepG2 cells caused cell death in a dose-dependent manner. Interestingly, exposure of
HepG2 cells to APAP elicited significant release of ATP to the supernatant in levels that were high enough to
promote direct cytotoxicity to healthy primary hepatocytes or HepG2 cells. In agreement to our in vivo results,
apyrase treatment or blockage of P2 receptors reduced APAP cytotoxicity. Likewise, ATP exposure caused significant
higher intracellular Ca2+ signal in APAP-treated primary hepatocytes, which was reproduced in HepG2 cells.
Quantitative real time PCR showed that APAP-challenged HepG2 cells expressed higher levels of several purinergic
receptors, which may explain the hypersensitivity to extracellular ATP. This phenotype was confirmed in humans
analyzing liver biopsies from patients diagnosed with acute hepatic failure.
Conclusion: We suggest that under pathological conditions, ATP may act not only an immune system activator,
but also as a paracrine direct cytotoxic DAMP through the dysregulation of Ca2+ homeostasis.
Keywords
Liver injurySterile inflammation
Acetaminophen
Remote injury
Cell death
Immune system
Inflammation
Purinergic signaling
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