Abstract
Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling plays a dominant role in the pathogenesis of liver ischemia-reperfusion (IR) injury. Dexmedetomidine (Dex) protects the liver against IR injury via α2-adrenoceptor activation, but the contribution of TLR4 signaling remains unknown. The authors aimed to examine whether pretreatment with Dex produces hepatic protection and investigate the influence of Dex on TLR4/NF-κB signaling. Dex was given via intraperitoneal injection 30 min prior to orthotopic autologous liver transplantation (OALT) in rats, and three α2-adrenoceptor antagonists including atipamezole (a nonselective α2 receptor blocker), ARC-239 (a specific α2B/C blocker) and BRL-44408 (a specific α2A blocker) were injected intraperitoneally 10 min before Dex administration. Histopathologic evaluation of the liver and the measurement of serum alanine aminotransferase activity, TLR4/NF-κB expression in the liver, and pro-inflammatory factors (serum tumor necrosis factor-α, interleukin-1β and hepatic myeloperoxidase) concentrations were performed 8 h after OALT. Dex ameliorated liver injury after OALT probably by suppressing the TLR4/NF-κB pathway and decreasing inflammatory mediator levels. The protective effects of Dex were reversed by atipamezole and BRL-44408, but not by ARC-239, suggesting that these effects were mediated in part by the α2A subtype. In conclusion, Dex attenuates liver injury partly via the α2A-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-κB pathway.
Highlights
Ischemia-reperfusion (IR) injury in the liver remains a major problem during liver transplantation and resection surgery [1,2]
Most oafcothmepeleffteecαts2-AofRDaegxo,nsisutcwhitahsrtehmeaarnkaablgleesbiicn,dsiendgactaipvaec,ihtyyfpoortaelnl tshivreee, saunbdtyppoetse(nαt2iAa,lαn2Be,uarnodpαro2Ct)ective effectso,fathree mhuemdaiantαed2-AbRy [t2h0e].αM2oAs-taodfrtehneoecffeepcttsorofsDubexty, spuech[2a1s–t2h3e]a. nTahlgeerseifco, rseed, watieveh,yhpyoptohteenssiziveed, atnhdat Dex protecptsotaegnatiianlsnteIuRroipnrjuotreyctoivfetheeffelicvtse,rabreymacetdiviaatetidngbyththeeαα22AA--aaddrreennoocceepptotrorsusbutbytpyep[e2,1–a2n3d].tThheemrefeocrhea, nism is duewtoe hthyepostuhpespizredsstihoant oDfetxhperTotLeRct4s/aNgaFin-κstBIRiniflnajumrymoafttohreylicviercrubiyt.activating the α2A-adrenoceptor subtype, and the mechanism is due to the suppression of the Toll-like receptor 4 (TLR4)/NF-κB inflammatory circuit
In addition to its cytoprotective effects on the liver, our studies demonstrated that Dex suppressed the TLR4/NF-κB inflammatory signaling, as evidenced by the downregulation of the TLR4 and p65 proteins in the liver and the inhibited release of the pro-inflammatory cytokines (TNF-α and IL-1β) in the serum by Dex pre-treatment
Summary
Ischemia-reperfusion (IR) injury in the liver remains a major problem during liver transplantation and resection surgery [1,2]. The consequences of IR injury are significant. Liver IR involves a complex interaction of events that include Kupffer cell activation, neutrophil infiltration, the generation of reactive oxygen species, and the release of cytokines -TαL,RIsLa-r1eβw, aidnedlyIeLx-p6re(isnsetderolenutkheint-is6s)u)e[7o–f 1th0e].liDverru, gsuscihnhasibKiutipnfgfetrhceelalsc,thivepitaytoocfyttehse, TLR inflamafamncdtaotrhoekrpayaptspiycassBtteem(lNlaFtae-fκfBcoe)rldlasnpd[9o]st.uenbTstreiiagqglueebrneintnlgyefiuthcpeiraelTgeuLflRafetecpstastthhfweoraeyxtphlreeeasldsivisoentro,oaftshinedfloaacmttirmvaanattisoogrneynogifecnnmeusecaltehnadords of blockiinngflaTmLmRa4t/oNryFfa-κctBo-rrse(lia.et.e, dTNgFe-nαe,sIL[-61,β11, a,1n2d].IL-6 (interleukin-6)) [7,8,9,10]. NTahlgeerseifco, rseed, watieveh,yhpyoptohteenssiziveed, atnhdat Dex protecptsotaegnatiianlsnteIuRroipnrjuotreyctoivfetheeffelicvtse,rabreymacetdiviaatetidngbyththeeαα22AA--aaddrreennoocceepptotrorsusbutbytpyep[e2,1–a2n3d].tThheemrefeocrhea, nism is duewtoe hthyepostuhpespizredsstihoant oDfetxhperTotLeRct4s/aNgaFin-κstBIRiniflnajumrymoafttohreylicviercrubiyt.activating the α2A-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-κB inflammatory circuit Most oafcothmepeleffteecαts2-AofRDaegxo,nsisutcwhitahsrtehmeaarnkaablgleesbiicn,dsiendgactaipvaec,ihtyyfpoortaelnl tshivreee, saunbdtyppoetse(nαt2iAa,lαn2Be,uarnodpαro2Ct)ective effectso,fathree mhuemdaiantαed2-AbRy [t2h0e].αM2oAs-taodfrtehneoecffeepcttsorofsDubexty, spuech[2a1s–t2h3e]a. nTahlgeerseifco, rseed, watieveh,yhpyoptohteenssiziveed, atnhdat Dex protecptsotaegnatiianlsnteIuRroipnrjuotreyctoivfetheeffelicvtse,rabreymacetdiviaatetidngbyththeeαα22AA--aaddrreennoocceepptotrorsusbutbytpyep[e2,1–a2n3d].tThheemrefeocrhea, nism is duewtoe hthyepostuhpespizredsstihoant oDfetxhperTotLeRct4s/aNgaFin-κstBIRiniflnajumrymoafttohreylicviercrubiyt.activating the α2A-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-κB inflammatory circuit
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