| Traumatic hemorrhagic shock is a syndrome of organ dysfunction caused by severe trauma due to insufficient effective circulating blood volume and reduced tissue perfusion.It has a high incidence and mortality rate,and is the leading cause of death for people under 44 years of age in the United States.Therefore,early treatment of uncontrolled hemorrhagic shock is very important.At present,new concepts of early treatment of uncontrolled hemorrhagic shock have been proposed,including permissible hypotensive resuscitation and damage controlled resuscitation,which have improved the level of early treatment of trauma.However,both permissible low-pressure resuscitation and damage-controlled resuscitation need resuscitation fluids.In complex environments,liquid transportation is difficult,and adequate liquid resuscitation cannot be effectively achieved.At the same time,the current hypotensive resusuciation or damage control resusuciation has a short maintenance time of about 90 min,which cannot meet the requirements of evacuation for remote areas or complex areas.Therefore,it is of great significance to find anti-shock drugs that are less dependent on volume resuscitation and suitable for the early application of traumatic hemorrhagic shock,so as to prolong the golden treatment time and improve the early treatment level of uncontrolled hemorrhagic shock.Early research found that the average cross section,diameter and density of mitochondria increased were increased in the early stage of hemorrhagic shock in rats.With the prolongation of shock time,the cristae and matrix of mitochondria were obviously destroyed,the mitochondria swelled,the mitochondria were over divided into fragments,the mass of mitochondria were unbalanced,the mitochondrial permeability transition pore(MPTP)were opened,and the leakage of mitochondrial intermembrane space(IMS)increased.Furthermore,it can activate damp,Bax / Bak,Furthermore,it can activate injury associated molecular patterns(DAMP),activating split protein(Bax/Bak),initiate apoptosis and lead to cell death.It is indicated that the abnormality of mitochondrial morphology and function is closely related to the dysfunction of important organs and plays an important role in the occurrence and development of hemorrhagic shock.Recent studies showed that Mdivi-1,as a selective and cell-permeable inhibitor of mitochondrial division,can restore the structure and function of mitochondria by inhibiting mitochondrial division,apoptosis,cytochrome C release and ROS generation under a variety of pathological conditions,and then play a protective role in organ functions.However,it is still unclear whether its application in the early stage of uncontrolled hemorrhagic shock can prolong the golden treatment time of uncontrolled hemorrhagic shock,play a protective role in organ function,and improve the prognosis of patients with uncontrolled hemorrhagic shock.Therefore,this study intends to use the rat model of uncontrolled hemorrhagic shock to study the protective effect and mechanism of mitochondrial division inhibitor Mdivi-1 on the organ function of hemorrhagic shock in the early application,including the following two parts :(1)the protective effect and mechanism of Mdivi-1 on the organ function of uncontrolled hemorrhagic shock;(2)The effect of Mdivi-1 on prolonging the golden treatment time of rats with uncontrolled hemorrhagic shock.Experimental methods:(1)Uncontrolled hemorrhagic shock model was established in SD rats;(2)To detect the functional indexes of heart,liver and kidney organs;(3)The blood perfusion of organs was measured by laser speckle blood flow analyzer;(4)The changes of ROS and MDA were detected by the kit;(5)Mitochondrial respiration control rate was measured using a mitochondrial activity analyzer;(6)The morphology of cardiac mitochondria was observed by transmission electron microscopy.Research contents:Part I: Protective effect and mechanism of Mdivi-1 on organ function in rats with uncontrolled hemorrhagic shock1.Uncontrolled hemorrhagic shock model was established in SD rats.After blood pressure was reduced to 40 mm Hg,conventional fluid resuscitation,conventional fluid resuscitation combined with different doses of Mdivi-1(0.25 mg /kg,0.5mg /kg,1mg/kg)were given respectively to increase blood pressure to 50-60 mm Hg.Determinate hemostasis and fluid resuscitation were given after 1h maintenance,and the effects of different doses of Mdivi-1 on blood loss and infusion volume after 1h maintenance at low pressure(50-60 mm Hg)were observed and recorded.2.To observe the effects of different doses of Mdivi-1 on the organ functions of rats with uncontrolled hemorrhagic shock,including the effects on aspartate aminotransferase(AST),glutamate aminotransferase(ALT),serum creatinine(CREA),blood urea nitrogen(BUN),cardiac output and cardiac injury marker tro PONin(c Tn T);At the same time,the effects of different doses of Mdivi-1 on liver and kidney blood flow in rats with uncontrolled hemorrhagic shock were observed by laser speckle blood flow analyzer.The effect of mdivi-1on the morphology of myocardial tissue in rats with uncontrolled hemorrhagic shock was observed.3.The effects of different doses of Mdivi-1 on 72 h survival rate and survival time of rats with uncontrolled hemorrhagic shock were observed.4.The effects of different doses of Mdivi-1 on oxidative stress in rats with uncontrolled hemorrhagic shock were observed by detecting the content of ROS and MDA in heart,liver,kidney and other tissues.5.The effects of different doses of Mdivi-1 on the mitochondrial morphology of myocardial cells in rats with uncontrolled hemorrhagic shock were observed by transmission electron microscopy,and the control rates of mitochondrial respiration in heart,liver,kidney and intestine were detected by a mitochondrial activity analyzer to observe the effects of different doses of Mdivi-1 on the mitochondrial function of rats with uncontrolled hemorrhagic shock.Part II: Effect of Mdivi-1 on prolonging the golden treatment time of UHS rats1.Effects of partial Mdivi-1 on maintenance of low pressure resuscitation in rats with uncontrolled hemorrhagic shockIn the uncontrolled hemorrhagic shock model,the rats were killed after blood pressure was reduced to 40 mm Hg by conventional fluid resuscitation and conventional fluid resuscitation combined with different doses of Mdivi-1,respectively,to increase blood pressure to 50-60 mm Hg.The splenic artery was not ligated and hemostasis was not completed until blood pressure was lower than 30 mm Hg.The effects of different doses of MDIVI-1 on the maintenance time of low pressure(50-60 mm Hg)were observed and recorded.2.Effect of Mdivi-1 on prolonging the golden treatment time of rats with uncontrolled hemorrhagic shock.The survival rate and survival time after determined hemostasis and fluid resuscitation with different doses of Mdivi-1 were observed and recorded after maintained at low pressure(50-60 mm Hg)for 2h,and the effects of Mdivi-1 on blood loss,fluid demand and MAP after2 h resuscitation were also observed.Results:Part I: Protective effect and mechanism of Mdivi-1 on organ function in rats with uncontrolled hemorrhagic shock1.Addition of Mdivi-1 during conventional liquid resuscitation significantly reduced blood loss and fluid demand during 50-60 mm Hg low-pressure maintenance for 1h.Compared with the conventional liquid resuscitation group,blood loss in 0.5mg/kg Mdivi-1 group was reduced by 24.8%,and fluid demand during low-pressure maintenance was reduced by46.4%.2.Mdivi-1 administration during conventional fluid resuscitation significantly increased the blood flow of liver and kidney and improved liver and kidney function in rats with uncontrolled hemorrhagic shock.Compared with the conventional fluid resuscitation group,the blood flow of liver and kidney was significantly increased after Mdivi-1 administration,and ALT,CREA and BUN were significantly decreased.It alleviates myocardial injury and significantly reduces c Tn T and improves cardiac function.Pathological sections showed that compared with conventional fluid resuscitation,the interstitial edema of myocardial cells was reduced,the space of myocardial tissue was reduced,and the disorder of myocardial fiber arrangement was obviously restored in Mdivi-1 group.3.The survival rate and survival time of rats with uncontrolled hemorrhagic shock were significantly improved by the administration of MDIVI-1 during conventional fluid resuscitation.4.The administration of Mdivi-1 during routine fluid resuscitation can significantly reduce the production of ROS and MDA in various organs and tissues of shock rats,and reduce the oxidative stress injury of shock rats.5.Routine fluid resuscitation combined with mdivi-1 can significantly inhibit mitochondrial over-division in shock rats,reduce mitochondrial damage,and restore the density of mitochondrial matrix and clear ridge structure.At the same time,compared with the conventional liquid resuscitation group,Mdivi-1 can significantly increase the control rate of mitochondrial respiration in liver,kidney and intestine,and improve the mitochondrial function of shock rats.Part II: Effect of Mdivi-1 on prolonging the golden treatment time of uncontrolled hemorrhagic shock rats1.Routine fluid resuscitation combined with mdivi-1 significantly increased the maintenance time of blood pressure at 50-60 mm Hg before definitive hemostasis treatment in rats with uncontrolled hemorrhagic shock;2.Routine fluid resuscitation combined with Mdivi-1 significantly increased the 24 h survival rate of rats with uncontrolled hemorrhagic shock after low-pressure maintenance for2 h,extended the survival time,and improved MAP after fluid resuscitation.Conclusion:1.Mdivi-1 can significantly increase the maintenance time of low pressure in rats with uncontrolled hemorrhagic shock,and reduce blood loss and fluid demand during the maintenance stage of low pressure.2.Mdivi-1 can significantly increase the blood flow of organs in rats with uncontrolled hemorrhagic shock,improve the structure and function of vital organs,and then improve the survival rate of rats with uncontrolled hemorrhagic shock.3.Mdivi-1 can reduce oxidative stress damage in rats with shock,stabilize and improve the morphology and function of mitochondria in rats with uncontrolled hemorrhagic shock,and then play a protective role in rats with uncontrolled hemorrhagic shock.4.Mdivi-1 can prolong the golden treatment time of rats with uncontrolled hemorrhagic shock. |
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