Richardson Amir K, Samuvel Devadoss J, Krishnasamy Yasodha, Lemasters John J, Zhong Zhi
Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina Charleston, SC 29425, USA.
Department of Biochemistry and Molecular Biology, Medical University of South Carolina Charleston, SC 29425, USA.
Int J Physiol Pathophysiol Pharmacol. 2025 Aug 25;17(4):131-147. doi: 10.62347/JMWH4994. eCollection 2025.
Clinically, liver regeneration is often impaired by infections causing endotoxemia, although mechanisms are unclear. Since energy supply is essential for liver regeneration, we assessed whether formoterol (FMT), a β-adrenergic agonist that increases peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), the master regulator of mitochondrial biogenesis (MB), restores liver regeneration after partial hepatectomy (PHX) in endotoxin (LPS)-treated mice.
Mice underwent sham-operation, two-thirds PHX, PHX with LPS injection (PHX+LPS, 5 mg/kg, ), or PHX+LPS followed by FMT (0.1 mg/kg, ) after 2 h.
At 48 h after PHX, 5'-bromo-2'-deoxyuridine incorporation, mitotic cells, proliferating cell nuclear antigen, and cyclin-D1 markedly increased, signifying liver regeneration. By contrast, after PHX+LPS, liver regeneration was almost completely suppressed. FMT restored liver regeneration after PHX+LPS. PGC1α, mitochondrial transcription factor-A (controlling mitochondrial DNA replication/transcription), and mitochondrial oxidative phosphorylation proteins ATP synthase-β and NADH dehydrogenase-3 decreased after PHX+LPS, signifying suppressed MB. FMT largely reversed these effects. Mitochondrial oxidative stress stimulates inflammation by activating inflammasomes. In addition to promoting MB, PGC1α reportedly inhibits oxidative stress and inflammation. 8-Hydroxy-deoxyguanosine, NLRP3, and inflammatory cytokines increased after PHX+LPS, demonstrating increased oxidative stress and inflammasome activation. Many necro-inflammatory foci occurred in liver sections after PHX+LPS. FMT increased expression of antioxidant protein thioredoxin-2, decreased oxidative stress, and blunted inflammatory responses. Additionally, FMT decreased alanine aminotransferase release and necrosis caused by PHX+LPS.
FMT restores liver regeneration during endotoxemia and decreases liver injury and inflammation, most likely by increasing PGC1α. Therefore, FMT is a promising therapy for liver failure caused by loss of liver mass complicated with sepsis.
临床上，肝脏再生常因感染导致内毒素血症而受损，但其机制尚不清楚。由于能量供应对肝脏再生至关重要，我们评估了福莫特罗（FMT），一种可增加过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）及线粒体生物发生（MB）的主要调节因子，能否恢复内毒素（LPS）处理小鼠部分肝切除（PHX）后的肝脏再生。
小鼠接受假手术、三分之二肝切除、肝切除并注射LPS（PHX+LPS，5mg/kg）或肝切除+LPS后2小时给予FMT（0.1mg/kg）。
肝切除术后48小时，5'-溴-2'-脱氧尿苷掺入、有丝分裂细胞、增殖细胞核抗原和细胞周期蛋白D1显著增加，表明肝脏再生。相比之下，肝切除+LPS后，肝脏再生几乎完全受到抑制。FMT恢复了肝切除+LPS后的肝脏再生。肝切除+LPS后，PGC1α、线粒体转录因子A（控制线粒体DNA复制/转录）以及线粒体氧化磷酸化蛋白ATP合酶-β和NADH脱氢酶-3减少，表明MB受到抑制。FMT在很大程度上逆转了这些影响。线粒体氧化应激通过激活炎性小体刺激炎症。据报道，除了促进MB外，PGC1α还可抑制氧化应激和炎症。肝切除+LPS后，8-羟基脱氧鸟苷、NLRP3和炎性细胞因子增加，表明氧化应激和炎性小体激活增加。肝切除+LPS后肝切片出现许多坏死性炎症病灶。FMT增加抗氧化蛋白硫氧还蛋白-2的表达，降低氧化应激，并减弱炎症反应。此外，FMT减少了肝切除+LPS引起的丙氨酸转氨酶释放和坏死。
FMT可恢复内毒素血症期间的肝脏再生，并减少肝脏损伤和炎症，最可能是通过增加PGC1α实现的。因此，FMT是治疗因肝实质丧失并发脓毒症所致肝衰竭的一种有前景的疗法。
