Dexmedetomidine-mediated protection against septic liver injury depends on TLR4/MyD88/NF-κB signaling downregulation partly via cholinergic anti-inflammatory mechanisms.

Uncontrolled inflammatory responses exacerbate the pathogenesis of septic acute liver injury (ALI), posing a lethal threat to the host. Dexmedetomidine (DEX) has been reported to possess protective properties in inflammatory conditions. This study aimed to investigate whether DEX pretreatment exhibits hepatoprotection against ALI induced by lipopolysaccharide (LPS) in rats and determine its possible molecular mechanism. Septic ALI was induced by intravenous injection of LPS. The rats received DEX intraperitoneally 30 min before LPS administration. α-Bungarotoxin (α-BGT), a specific α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, was administered intraperitoneally 1 h before LPS exposure. The role of the vagus nerve was verified by performing unilateral cervical vagotomy or sham surgery before sepsis. The expression of α7nAChR, toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), and cleaved caspase-3 increased, peaking 24 h during sepsis. DEX enhanced α7nAChR activation and reduced TLR4 expression upon challenge with LPS. DEX significantly prevented LPS-induced ALI, which was associated with increased survival, the mitigation of pathological changes, the attenuation of inflammatory cytokine expression and apoptosis, and the downregulation of TLR4/MyD88/NF-κB pathway. Moreover, the hepatoprotective effect of DEX was abolished by α-BGT. Further investigation established that vagotomy, compared to sham surgery, triggered more severe pathogenic manifestations and higher proinflammatory cytokine levels. The inhibitory effects of DEX were shown in sham-operated rats but not in vagotomized rats. Our data highlight the pivotal function of α7nAChR and intact vagus nerves in protecting against LPS-induced ALI through inhibiting the TLR4/MyD88/NF-κB signaling pathway upon pretreatment with DEX. A proposed model of the regulatory anti-inflammatory role of DEX in septic liver injury. Under septic conditions, α7nAChR-mediated anti-inflammatory and TLR4-mediated proinflammatory pathways are activated, and a massive number of proinflammatory cytokines are released. DEX suppresses proinflammatory cytokines by upregulating α7nAChR and ACh and then inhibiting the TLR4/MyD88/NF-κB pathway, resulting in inflammation inhibition. The effects of DEX are abrogated by the specific α7nAChR antagonist α-BGT or by vagotomy. Thus, the protective effect of DEX is attained through an α7nAChR-dependent process and requires intact vagus nerves. Unlabelled Image • DEX alleviates liver injury induced by LPS. • DEX prevents cytokine production and inhibits apoptosis. • DEX inhibits the LPS-induced upregulation of the TLR4/MyD88/NF-κB pathway. • DEX possesses anti-inflammatory properties via α7nAChR-mediated signaling and requires intact vagus nerves. [ABSTRACT FROM AUTHOR]