The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.
The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.
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血小板生成素模拟物 JNJ-26366821 可减少对乙酰氨基酚诱导的小鼠肝损伤后的晚期损伤并加速肝脏恢复。
DOI：
10.1007/s00204-024-03725-2
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发表时间：
2024
影响因子：
6.1
通讯作者：
Jaeschke,Hartmut
中科院分区：
文献类型：
--
作者：
Adelusi,OlamideB;Akakpo,JephteY;Eichenbaum,Gary;Sadaff,Ejaz;Ramachandran,Anup;Jaeschke,Hartmut
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），防止损伤，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，TPO受体存在于肝窦内皮细胞以及巨核细胞和血小板上，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、NAC或4-MP在禁食雄性C57 BL/6 J小鼠中300 mg/kg APAP过量给药后2 h给药时可在肝脏中提供保护和再生作用的程度。TPOm没有影响蛋白加合物，氧化应激，DNA断裂和肝坏死后12小时APAP。相反，TPOm处理在24小时是有益的，即，所有损伤参数降低了42- 48%。重要的是，如坏死区域周围的PCNA阳性肝细胞所示，TPOm使增殖增加100%。当TPOm治疗延迟6小时，对损伤没有影响，但增殖作用仍然明显。与此相反，4 MP和NAC处理后2小时APAP显着减弱所有损伤参数在24小时，但未能提高肝细胞增殖。因此，TPOm在APAP后24小时阻止了肝损伤的进展，并加速了对肝脏恢复至关重要的增殖反应的发生。
Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such asN-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.