对乙酰氨基酚(APAP)诱导的肝毒性包括损伤和恢复阶段。虽然药物干预,如N-乙酰半胱氨酸(NAC)和4-甲基吡唑(4-MP),预防伤害没有促进恢复的疗法。JNJ-26366821(TPOm)是一种新型的血小板生成素模拟肽,与内源性血小板生成素(TPO)没有序列同源性。内源性血小板生成素由肝细胞产生,TPO受体除巨核细胞和血小板外,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了有益的作用。因此,我们评估了TPOM的程度,当在禁食的雄性C57BL/6J小鼠中APAP过量300mg/kg后2小时施用时,NAC或4-MP可以在肝脏中提供保护和再生作用。TPOm不影响蛋白质加合物,氧化应激,APAP后12小时内DNA片段化和肝坏死。相比之下,TPOm治疗在24小时是有益的,即,所有损伤参数均降低了42-48%.重要的是,如坏死区域周围的PCNA阳性肝细胞所示,TPOm将增殖增强了100%。当TPOm治疗延迟6h时,对伤势没有影响,但是增殖效应仍然很明显。相比之下,APAP后2小时处理的4MP和NAC在24小时显着减弱了所有损伤参数,但未能增强肝细胞增殖。因此,TPOm可在APAP后24小时内阻止肝损伤的进展,并加速增殖反应的发生,这对于肝脏恢复至关重要。
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.