| Objective:Hepatic ischemia-reperfusion(I/R)injury is an important clinical issue.It has been implicated in the pathogenesis of a variety of clinical conditions including trauma,thermal injury,hypovolemic and endotoxin shock,reconstructive vascular surgery,liver transplantation,and liver resectional surgery.Leukotriene C4(LTC4)is arachidonic acid-derived preinflammatory factors which are mainly metabolized in liver.Studies have shown that abnormally increased LTC4 production in the early phase of hepatic I/R injury is involved in membrane lipid peroxidation and liver dysfunction and morphological damage which reduce LTC4 metabolite excretion,and in return LTC4 accumulation may increase the existed inflammatory lesions of liver caused by I/R.Our previous findings suggest that abnormal LTC4 accumulation during hepatic I/R injury can be partially caused by LTC4 synthase(LTC4S)over-expressions and its activities augment.Ischemic preconditioning(IP),which defined as a brief period of liver ischemia followed by reperfusion,has been demonstrated to protect against a following prolonged I/R injury.However,some contradictory reports also presented and the mechanisms underlying IP protecting against hepatic I/R is not fully clear.A lot of researches have confirmed the effects of IP in liver transplantation,which include the reduction of blood loss in hepatectomy,a markedly diminished oxidant generation and oxidative reactions,intraoperative hemodynamic stability and its significant role in liver regeneration.It is well known that NO acted as an important role in the mechanisms of IP protecting against I/R injury.But up to now,it is remained to be further clarified whether IP can regulate LTC4 products via a NO activation pathway.Using a nonspecific nitric oxide synthase(NOS)inhibitor,L-NAME,this topic studied IP actions on LTC4 concentration,LTC4 S,and implored the roles of NO in IP regulating the abnormal increase of LTC4 in the early phase of liver I/R injury in order to further elucidate the underlying molecular mechanisms in it.These findings will provide a new experimental and theoretic evidences for the treatment of liver transplantation and liver resectional surgery.Methods:Adult male Sprague-Dawley rats were divided into 4 groups: sham group(Sham),ischemic-reperfusion group(I/R),IP group and L-NAME groups with 6 rats in each group.Liver were subjected to 60 min of partial hepatic ischemia followed by 5 h of reperfusion,saline was administered intravenously.LTC4 concentration,the activities and expressions of LTC4 S were examined with RP-HPLC,immunoblot and immunohistochemistry methods.Liver damage was assessed by serum ALT,AST measurements and histological observation.Liver tissue SOD activity,MDA and GSH level were employed to evaluate lipid peroxidation in these pathological processes.Results:Compared with I/R group,IP markedly decreased LTC4 concentration,reduced the gene and protein expressions of LTC4 S and inhibited the LTC4 S activities in rat liver(P<0.05).The declines of ALT and AST activities in serum and liver MDA level(P<0.05),together with the increases of SOD activity and GSH level in hepatic tissue(P<0.05),and a less histological structure damage in IP groups were also observed.Immunohistochemistry staining showed that the LTC4 S positive expressions on hepatocytes and sinusoidal endothelial cells in IP group were significantly lower than those in I/R group.All these effects of IP were abolished by L-NAME,a nonspecific NOS inhibitor.Conclusions:1?The inhibition of IP on the increased LTC4 production may also be related to the improvement of liver function,membrane lipid peroxidation,oxidative stress and liver tissue structure,thereby increasing LTC4 excretion..2?These findings suggest for the first time that IP may down-regulate the expression of LTC4 S gene and protein to reduce the abnormal accumulation of LTC4 during liver I/R injury through the NO activation pathway,thus protecting the liver from I/R damage. |
PDF Full Text Request