Figure 7

Proposed mechanism: 1: Under physiological conditions, extracellular ATP regulates several intracellular signaling pathways, which involves also calcium compartmentalization. 2–3: Acetaminophen incubation directly causes hepatocyte necrosis, calcium imbalance and further ATP release. 4: In parallel, challenged viable hepatocytes up-regulate several purinergic receptors, probably as a regulatory homeostatic strategy, causing ATP hyper-responsiveness. Binding of extracellular ATP to purinergic receptors increases intracellular Ca²⁺ and pulses, which accounted to additional cell necrosis, reverberating APAP-induced death. Dampening of extracellular ATP signalling or reducing intracellular Ca²⁺ availability significantly reduced hepatocyte necrosis. Data from FHF patients suggest that a similar necrosis-amplification pathway may be involved in organ injury progression.