Pharmacological preconditioning with the cellular stress inducer thapsigargin protects against experimental sepsis. (March 2019)

• Record Type: Journal Article
• Authors: Wei, Yaping; Meng, Mei; Tian, Zhenyu; Xie, Fubo; Yin, Qihui; Dai, Chaochao; Wang, Jingjing; Zhang, Qunye; Liu, Yu; Liu, Chang; Yan, Feng; Jiang, Fan; Guo, Xiaosun
• Is Part Of: Pharmacological research. Volume 141(2019)
• Page Start: 114
• Page End: 122
• Publication Date: 2019-03
• Subjects: TNF tumor necrosis factor -- IL interleukin -- TG thapsigargin -- SERCA sarcoendoplasmic reticulum -- ER endoplasmic reticulum -- LPS lipopolysaccharides -- CLP cecal ligation and puncture -- iNOS inducible nitric oxide synthase -- NO nitric oxide -- GRP78 78 kDa glucose-regulated protein -- eIF2α eukaryotic initiation factor 2α -- JNK c-Jun N-terminal kinase -- NF-κB nuclear factor-κB -- CHOP C/EBP homologous protein -- mTOR the mammalian target of rapamycin -- 4-PBA 4-phenylbutyric acid -- AMPK AMP-activated protein kinase -- TLR4 Toll-like receptor 4; Thapsigargin (CID: 446378) -- 4-Phenylbutyric acid (CID:4775); Thapsigargin -- Pharmacological preconditioning -- Sepsis -- Systemic inflammation response -- mTOR -- Protein translational efficiency; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.12.017
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Previous studies have shown that pretreatment with thapsigargin (TG), a cellular stress inducer, produced potent protective actions against various pathologic injuries. So far there is no information on the effects of TG on the development of bacterial sepsis. Using lipopolysaccharides- and cecal ligation/puncture-induced sepsis models in mice, we demonstrated that preconditioning with a single bolus administration of TG conferred significant improvements in survival. The beneficial effects of TG were not mediated by ER stress induction or changes in Toll-like receptor 4 signaling. In vivo and in cultured macrophages, we identified that TG reduced the protein production of pro-inflammatory cytokines, but exhibited no significant effects on steady state levels of their transcriptions. Direct measurement on the fraction of polysome-bound mRNAs revealed that TG reduced the translational efficiency of pro-inflammatory cytokines in macrophages. Moreover, we provided evidence suggesting that repression of the mTOR (the mammalian target of rapamycin) signaling pathway, but not activation of the PERK (protein kinase R-like endoplasmic reticulum kinase)-eIF2α (eukaryotic initiation factor 2α) pathway, might be involved in mediating the TG effects on cytokine production. In summary, our results support that pharmacological preconditioning with TG may represent a novel strategy to prevent sepsis-induced mortality and organ injuries.