Intervention Effect Of Simvastatin On Inflammatory Cytokine Responses Of Peripheral Blood In A Rat Fracture Model By Different Administration Methods

Objective:To evaluate the intervention effects of different methods of simvastatin administration on inflammatory cytokine responses of peripheral blood in fractures of rats.Methods:Forty-eight 10-week old male Sprague-Dawley(SD)rats were randomly divided into 4 groups.All rats established the rib fracture model.The rats in experimental group were divide into three groups(short-term administration;tapering administration;long-term administration)according to the dose of 10mg/(kg·d)simvastatin.Rats were administered with equivalent DMSO as control.The drugs were administered orally for four weeks.After administration 1,2,4 weeks,IL-1β,IL-6 and TNF-a and VEGF in peripheral blood are quantitatively by ELISA tests to evaluate the effects of different dosage of simvastatin on the fracture healing.After administration 1,2,4 weeks,X-ray analysis was taken to observe the fracture healing.Results:Expression of inflammatory factor IL-1β:After administration 1 week,the levels of IL-1β decreased more in intervention group than in control group.That means simvastatin can effectively reduce the expression of IL-1β at early stage of trauma.After administration 2 weeks,the expression of IL-1β in short-term administration group showed an increasing trend and reached its peak.We speculated that inflammatory factor rebound elevated after drug withdrawal.Expression of inflammatory factor IL-6:The expression of IL-6 in tapering administration group and long-term administration group was lower than that of control group.After administration 4 weeks,tapering administration group and control group have a significant statistic difference in the expression of IL-6(P<0.05).In short-term administration group,the levels of IL-6 and IL-1β showed similarly variable tendency,after administration 2 weeks,the expression of IL-6 reached its peak and higher than control group.After administration 4 weeks,the expression of IL-6 was lower than control group and had a significant statistic difference(P<0.05).Expression of inflammatory factor TNF-a:In tapering administration group and long-term administration group,the expression of TNF-a was markedly lower than that of control group.After administration 4 weeks,the levels of TNF-a was lower in intervention than in control.In short-term administration group,the expression of TNF-a was higher than other groups after administration 1,2 weeks;the expression of TNF-a reached its peak after administration 2 weeks;the tendency were similarly with IL-1βand IL-6.Expression of plasma VEGF:After administration 1 week,the levels of VEGF increased significantly in intervention group than in control group(P<0.001).After administration 2 week,the expression of VEGF in short-term administration group and long-term administration group was higher than that of control group(P<0.05).In short-term administration group,the level of VEGF was continuously decreasing.Short-term administration after fractured one week,the expression levels of IL-1β,IL-6,and TNF-a shows rebound elevated.Compared with control and Short-term administration,the expression levels of IL-1β,IL-6,and TNF-a were lower in those of long-term administration and tapering administration.As tapering administration,the treatment effect was more significant.X-ray:Results showed that fracture line in the simvastatin intervention group was less distincted after fractured four week,density of bony callus was higher than that of control group.Conclusion:Simvastatin tapering administration has certain effect on reducing the inflammatory cytokine response,it shows potential ability to promote fracture healing.Simvastatin short-term administration,inflammatory factor rebound elevated after drug withdrawal.The continuously high level expression of proinflammatory cytokines may lead to chronic inflammation and delayed fracture healing.Simvastatin long-term administration can reduce the expression of proinflammatory factors during fracture healing,but may have inflammatory factor rebound elevated after drug withdrawal.