TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.
MouseChemical/toxinC57BL/6J, plus AhCre Mdm2 flox, LSL-TGFbetaR1-CA, LysMCre Tgfb1 flox and p21-deficient linesMale and femaleOral gavageSB525334 10 mg/kg twice daily; AZ12601011 50 mg/kg twice da…Given at the time of acetaminophen dosing, or delayed to 12 hours after acetami…
Model: Acetaminophen-induced acute liver injury (350, 450 or 525 mg/kg by single intraperitoneal injection after a 10 hour fast) and carbon tetrachloride injury (1 mL/kg single dose, or 0.75 mL/kg weekly for 8 weeks)
TGF-beta receptor 1 inhibition reduced hepatocellular senescence, restored a proportionate perinecrotic regenerative response, reduced jaundice and permitted survival after an otherwise lethal 525 mg/kg acetaminophen dose, with benefit retained when treatment was delayed to 12 hours, beyond the eff…
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