Avitinib抑制NLRP3炎症小体活化并改善小鼠感染性休克

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Avitinib suppresses NLRP3 inflammasome activation and ameliorates septic shock in mice

SHANGFeifeiiokeG²Ouian，nnAn，GnqnG 1AnhuiProincialKybatoryfnloginoicisesgbuedicalesityngbu3al Laboratory，rstAfiliatedHospitalofengbuedicaliersityengbu3o4，ina

Abstract：ObjectiveToinvestigatetheefectofavitinibforsuppressingNLRP3inflammasomeactivationandaleviating septicshockandexploretheunderlyingmechanism.MethodsMousebonemarow-derivedmacrophages （BMDM），human monocyticleukemiacelineTHP-1，andperipheralbloodmononuclearcells（BMC）isolatedfromhealthyvolunteeswere pre-treated withavitinib，followed byactivationofthecanonicalNLRP3inflammasomeusingagonistsincluding nigericin， monosodiumurate （MSU）crystals，oradenosine triphosphate （ATP）.Non-canonical NLRP3 inflammasomeactivation was induced via intracellar transfectionof lipopolysacharide （LPS）. Western bloting wasusedtodetectthesecretoryprotein markers of NLRP3 inflammasome activation and assesspyroptosis，and the levelsof inflammatory cytokines incellculture supernatantweredeterminedwithELISA.InamousemodelofLPS-inducedsepticshock，theefectofavitinibtreatmenton thelevelsofinflammatorycytokines inserumandperitoneallavagefluid wereexaminedwithEISAandsurvivalcurvesof themicewereplottedusingtheKaplan-Meiermethod.ResultsAvitinibsignificantlyinhibitedNLRP3inflammasome activationinmultiplecelltypes，anddose-dependentlyreduced IL-1βsecretionandcaspase-1cleavagewhilesuppressing GSDMD-mediated pyroptosiswithoutobviouslyaffectingIL-6or TNF- α levels.In the mouse models of LPS-induced septic shock，avitinibsignificantlylowered IL-1βlevelsinserumandperitonealfluidandextendedsurvivaltimeofthemice. Conclusion Avitinib suppresses NLRP3 inflammasome activation and alleviates septic shock in mice.

Keywords：avitinib;NLRP3inflammasome;EGFRinhibitor;septic shock

NLRP3炎症小体是一种检测外源性致病性侵袭和内源性细胞损伤的重要传感器，由3个主要成分组成，分别是NOD样受体热蛋白结构域相关蛋白3（NLRP3）凋亡相关斑点样蛋白ASC（PYCARD）以及效应器caspase-1构成。（剩余16202字）