Pharmacological Preconditioning With The Cellular Stress Inducer Thapsigargin Protects Against Experimental Sepsis

BackgroundSepsis(sepsis)is a systemic inflammatory response caused by an infection that manifests itself as a life-threatening organ dysfunction caused by host response disorders.Sepsis is a dangerous condition with a high mortality rate.In recent years,although anti-infective treatment and organ function support technology have made some progress,the total mortality of sepsis is still more than 30%.The current treatment of sepsis is mainly directed at immune regulation and anti-infection.However,due to the complexity and obvious individual differences in the immune and inflammatory response in patients with sepsis,clinical trials for anti-inflammatory treatment in the past have failed to show significant clinical prognosis.Therefore,it is of great significance to find new targets for effective treatment and prevention of the development of sepsis.Thapsigargin(TG)is an inducer of endoplasmic reticulum(ER)stress in endoplasmic reticulum.Previous studies have shown that pretreatment with TG produces protection against a variety of stress injuries.So far,there is no information on the effect of TG pretreatment on the development of sepsis.ObjectiveThapsigargin(TG)is an inducer of endoplasmic reticulum(ER)stress.Previous studies have shown that pretreatment with TG produced potent protective actions against various pathologic injuries.So far there is no information on the effects of TG on the development of severe sepsis.MethodsThe model of sepsis induced by sepsis in mice and cecal ligation and puncture(CLP)was induced by lipopolysaccharide(LPS)at the overall level.Preconditioning application of thapsigargin was intraperitoneally administered 15 hours prior to LPS treatment.The biological mechanisms of inflammatory responses were studied at the cellular level using western blot,real-time PCR,and ELISA.ResultsTG preconditioning confers significant improvements in survival.The beneficial effects of TG were not mediated by ER stress induction or changes in Toll-like receptor 4 signaling.Both in vivo and in vitro,we identified that TG reduced the protein production of pro-inflammatory cytokines,but exhibited no significant effects on their mRNA levels.Direct measurement on the fraction of polysome-bound mRNAs has revealed that TG reduces the translational efficiency of macrophage cytokine expressions.Moreover,we provided evidence suggesting that repression of the mTOR(the mammalian target of rapamycin)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.ConclusionsOur results support that pharmacological preconditioning with TG may represent a novel strategy to prevent sepsis-induced mortality and organ injuries.