The Role Of Dexmedetomidine In Secondary Lung Injury Induced By Sepsis And The Underlying Mechanism

Objective To explore the action of dexmedetomidine on sepsis at different stages and the postulated mechanism.Methods and Protocols Model:Cecal Ligation and Perforation(CLP) sepstic rat model. Experimet protocol:149SD(Sprague Dawley) rats were randomly allocated into5groups, blank control group(n=22, without any treatment), sham operation group(n=22, laparotomy and separate cecal artery with retension of2drainage rubber strips), CLP operation group(n=35, cecal artery separation and CLP operation with2rubber drainage strips), dexmedetomidine pretreatment group(n=35, i.p Dex lOug/kg10min after anesthesia,the others as CLP operation group), atepamezole antagonizing group(n=35, i.p250ug/kg atepamezole when anesthesia, the others as Dex pretreatment group). Measurements:record survival rate, anal temperature and disease severity (according to "murine sepsis score" scoring scale,MSS) within24hours after treatments (n=10in blank and sham group, n=15in the others), and euthanized at4h,8h,12h,24h after treatment(n=3at every timepoint in blank and sham group,n=5in the others) to harvest left ventral blood to analyse ABG, to dissect lungs for pathological observation(HE and pathological scoring) and caveolin-1analysis(westernblot). Statistic analysis:With SSPS22.0(IBM, USA) software for statistical analysis. All data presented with Mean±SD. Comparing temperature and MSS scores within groups with linear mixed model (repeated covariance type compound diagonal), the others with complete random design Post Hoc analysis (LSD), Variance homogeneity analysis with Levene’s or Bartletts analysis. Survival data nanalyzed with log-rank□2test, survival curve analysis with Kaplan Meier analysis. Significant level defined as two-tailed a=0.05. Results:(1) Dexmedetomidine(DEX) pretreatment could significantly improve survival rate from20%to40%(P<0.05, vs. C), the addition of atepamezole(AMZ) didn’t antagonize this protective effect(P<0.05,vs. CD).(2) DEX pretreatment effectively attenuated fever and lung pathological changes (P<0.05vs. C) but affected disease manifestations less (P>0.05vs. C), AMZ antagonized protective action of DEX on pulmonary inflammatory changes except mitigating lung edema(P<0.05vs. CD) and disease symptoms (P<0.05vs. CD).(3) CLP-induced sepsis could significantlydown-regulate and change circadian expression mode of caveolin-1(P<0.05vs. CT/S). DEX pretreatment effectively preserved this mode and up-regulated caveolin-1compared with C group(P<0.05). AMZ antagonized the up-regulatory effect of DEX and decreased caveolin-1experession(P<0.05vs. CD).Conclusion:DEX pretreatment significantly protected rats from septic insults and lung injury. This may act partly through the preservation of caveolin-1expression mediated by the activation of a2adrenoceptor and imidazoline receptors.