Protective Effect Of Dexmedetomidine On Liver Injury Induced By LPS And Its Related Mechanisms

Endotoxemia is a systemic infectious disease that occurs frequently in veterinary clinic and has a high mortality rate.Exploring effective prevention and treatment of drugs and elucidating key pharmacodynamic mechanisms are the focus of research in this field.Previous studies of endotoxemia have focused on the lungs and kidneys.As an important detoxification organ in the body,the liver plays an important role in the course of endotoxemia.Endotoxemia is an inflammation.The pathophysiological mechanism of septic acute liver injury(SALI)is concentrated in the inflammatory response.In recent years,the focus of research has begun to shift to oxidative stress injury and liver cell apoptosis.Dexmedetomidine(DEX)is a pre-mass analgesic and sedative that is commonly used in small animals.It has anti-inflammatory,anti-oxidative and anti-apoptotic effects.In this study,48 healthy male SD rats were random Ly divided into 8 groups: group C,group M,group D,group A,group G,group CD,group CA and group CS.Groups M,D,A,and G were intraperitoneally injected with 10 mg/kg lipopolysaccharide(LPS)at a concentration of 10 mg/m L according to rat body weight.At 30 min before LPS injection,D and A groups were intraperitoneally injected with 30 ?g/kg DEX at a concentration of 30 ?g/m L according to rat body weight,and G group was intraperitoneally injected with 10 mg/kg GSK-3? inhibitor SB216763 at a concentration of 10 mg/m L according to rat body weight.At 30 minutes before DEX injection,group A was given intraperitoneal injection of 250 ?g/kg of atipamezole(ATI)at a concentration of 250 ?g/m L according to rat body weight.The C group was given no treatment.The CD group was intraperitoneally injected with 30 ?g/kg DEX at a concentration of 30 ?g/m L according to rat body weight.The CA group was given intraperitoneal injection of 250 ?g/kg of ATI at a concentration of 250 ?g/m L according to rat body weight,and the CS group was intraperitoneally injected with 10 mg/kg GSK-3? inhibitor SB216763 solvent at a concentration of 10 mg/m L according to rat body weight.After 4 hours of drug action,the rats were inhaled and anesthetized,then the heart was collected and the liver was taken out.Through the following three parts: rat liver function test and liver histopathology observation,liver tissue oxidative stress index detection and serum related inflammatory cytokine detection,a series of tests for the changes of m RNA and protein expression of related molecular markers in the possible protective mechanism of DEX.To explore the protective mechanism and pharmacodynamics of DEX on rat SALI.(1)The results of liver function tests showed that the ALT content of group C was the lowest among all groups,and the ALT level of group M was the highest.The ALT level of group D was lower than that of group M,the difference was extremely significant.There was almost no difference compared with the D group,and the ALT of the G group was higher than that of the M group.The trend of AST content was basically consistent with ALT,but the A group was higher than the D group and the difference was significant.Hepatic histopathological sections were observed after HE staining,the hepatic lobule structure of group C was clear,no hepatocyte degeneration or necrosis,no inflammatory cell infiltration,liver tissue necrosis in liver tissue of group M and A,a small amount of vacuolar degeneration,small amount of inflammatory cells infiltrating the liver sinus,liver tissue congestion,improvement in group D and group G,no significant damage in CD,CA and CS groups.(2)The results of oxidative stress indicators are as follows,the MDA and ROS levels in the M and A groups were higher than those in the other groups,and the difference was extremely significant.The other groups had lower MDA and ROS levels.Statistically,the trends between SOD and GSH groups were completely opposite to those of MDA and ROS.The serum inflammatory factor C group had the lowest TNF-? content,M group extremely significant increased,D group compared with M group significantly decreased,group A and D group extremely significant increased,the G group was significantly decreased compared with the M group.The overall trend of IL-6 was consistent with TNF-?,except that the D group was extremely significant lower than the M group.The trend and difference of IL-1? and IL-18 are consistent with IL-6.(3)The results of immunohistochemical localization showed that Nrf2 protein did play a role in nuclear access.The protein expression of the M group was extremely significant lower than that of the C group,and the protein expression of the D group was extremely significant higher than that of the M group.The protein expression of group A was extremely significant lower than that of group D,and the protein expression of group G was extremely significant higher than that of group M.The results of immunohistochemical sectioning of P53 and c-caspase-3 also showed an effect on the nucleus and the trend was opposite to that of Nrf2.The trend of Nrf2 and P53 in RT-PCR is consistent with the trend of immunohistochemistry.WB results showed that LPS has an inhibitory effect on the expression of antioxidation and anti-apoptosis-related proteins,DEX and GSK-3? inhibitor SB216763 had an up-regulation effect.ATI could reverse the protective effect of DEX.LPS promotes the expression of pro-apoptotic proteins,and DEX and SB216763 have a down-regulation effect on pro-apoptotic proteins.ATI can still reverse the protective effect of DEX.Comprehensive analysis of experimental data shows that ?2 adrenergic receptor(?2-AR)plays an important antagonistic role in the protective effect of DEX on hepatic oxidative stress and apoptosis,and DEX regulates GSK-3?/MKP-1/Nrf2 pathway produces antioxidant and anti-apoptotic effects.It is concluded that DEX has a protective effect on SALI and functions by regulating GSK-3? by ?2-AR.