Formoterol promotes mitochondrial biogenesis, improves liver regeneration, and suppresses liver injury and inflammation after liver resection in mice with endotoxemia.

objectivesClinically, 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

methodsMice underwent sham-operation, two-thirds PHX, PHX with LPS injection (PHX+LPS, 5 mg/kg,

resultsAt 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.

conclusionsFMT 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.