Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42–48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.

对乙酰氨基酚 (APAP) 引起的肝毒性包括损伤和恢复阶段。虽然N-乙酰半胱氨酸 (NAC) 和 4-甲基吡唑 (4-MP)等药物干预可以预防损伤，但没有促进恢复的治疗方法。 JNJ-26366821 (TPOm) 是一种新型血小板生成素模拟肽，与内源性血小板生成素 (TPO) 无序列同源性。内源性血小板生成素由肝细胞产生，除了巨核细胞和血小板外，TPO 受体还存在于肝窦内皮细胞上，我们假设肝脏中 TPO 受体的 TPOm 活性在肝损伤后提供有益的作用。因此，我们评估了禁食的雄性 C57BL/6J 小鼠在过量服用 300 mg/kg APAP 2 小时后，TPOm、NAC 或 4-MP 对肝脏提供保护和再生作用的程度。 APAP 后 12 小时内，TPOm 不会影响蛋白质加合物、氧化应激、DNA 断裂和肝坏死。相比之下，TPOm 治疗在 24 小时时是有益的，即所有损伤参数降低了 42-48%。重要的是，坏死区域周围的 PCNA 阳性肝细胞表明，TPOm 使增殖增强了 100%。当TPOm治疗延迟6小时时，对损伤没有影响，但增殖作用仍然明显。相比之下，APAP 后 2 小时处理的 4MP 和 NAC 显​​着减弱了 24 小时时的所有损伤参数，但未能增强肝细胞增殖。因此，TPOm 可在 APAP 后 24 小时阻止肝损伤的进展，并加速增殖反应的发生，这对于肝脏恢复至关重要。