| Hepatic ischemia reperfusion injury (hereinafter to be referred as I/R) refers to thathepatic tissue cells are ischemic for a period of time and then recover for reperfusion.This could not recover its original functions and structures. Moreover, this aggravatesits functional disorder and structural injuries. I/R is a most common pathologicalprocess in liver diseases, which can be seen normally in liver transplantation, livertumors hepatectomy, hepatic trauma and hemorrhagic shock, etc. And I/R also couldlead serious liver and other organs funktionelle Schwache which is also one of theimportant reasons of surgery failure and patients death. Therefore, discussions on theoccurence and development process of I/R and protective relative elements andmolecules mechanism of I/R, there is important significance of improving our nationalliver diseases curing level on revealing its occurence and development process andprotective accurate molecules mechanism and looking for prevention and curing ofnew-type medicaments for hepatic ischemia reperfusion injury.Currently, operation treatment is the best choice to cure primary and secondaryliver tumors. Due to the complex vascularity and rich blood supply, it is very difficult tocontrol the bleeding during the operations. More and more clinical practices prove thatmassive transfusion during the operations could lead to the increasing theafter-operation death and complication occurrence and reducing the long-term survivalpercentage of patients who are suffering liver cancers. Hence, blocking the blood supplyto liver plays an important role during the operations. Nowadays, the most commonlyused method is Pringle method for blocking the blood supply to liver during theoperations which can effectively control the bleeding occured during the operation. Atthe same time, the liver tissue has high occurance of I/R and also could lead seriouscomplication such as liver failure after the operation. How to seasonally choose the blocking of the blood supply to liver based on a patient’s condition has an importanteffect on the recovery of the patient after the operations. As a result, the method ofselective blocking blood supply to liver including hemihepatic vascular occlusion,regional occlusion, and pure portal vein can effectively limit the bleeding during theoperation, and also can contribute to the liver functional recovery.Cyclooxygenase (hereinafter to be referred as COX) and Thromboxane (hereinafterto be referred as AA) synthesize the key rate-limiting enzyme. Prostaglandin(hereinafter to be referred as PG) and Thromboxane (hereinafter to be referred as TX).COX normally exists in tissues in two hypotypes. COX-1is structural type existing inmost organs and catalyzing to generate the Prostaglandin for normal physiologicfunctions needed. And COX-2is inducible type with extremely low compositions inmost organs under normal circumstance but increased obviously during inflammation,tumors and ischemia reperfusion. Researches shows that COX-2took part in theoccurence, development and has close relationship with prognosis.Celecoxib is an selective inhibitor of COX-2with its chemical name4-[5-cresyl-3-(trifluoromethyl)-1-H-pyrazol-1-radical] benzene sulfonamide. It can inhibit the highexpression of COX-2and consequently inhibit the balance of the rate of metabolitesPGI2and TXA2(i.e. TXA2/PGI2) of arachidonic acid. The aim is to reduce theinflammation reactions, improve microcirculation, relieve tissues injury and cellularedema so that to alleviate hepatic ischemia reperfusion injury. Clinically it is mainlyused for the treatment of osteoarthritis and rheumatoid arthritis. The studies on thecerebral ischemia reperfusion injury show that it possibly reduces the rate ofTXA2/PGI2to reduce the inflammation reactions, improve microcirculation, relievebrain injury and cerebral edema, and reduce the production of oxygen radicals toenhance SOD activity in order to cerebral protection functions. Currently, there is litterdirect studies on COX-2to ischemia reperfusion injury and many questions are still notclarified clearly. By adding different dose of celecoxib into the established model ofrates hepatic ischemia reperfusion to control COX-2activity, this experimentdetermined the expression level of COX-2, p-Stat3(pTry705) and so on in the rateslivers of each group after ischemia reperfusion, and furthermore discussed the effectsand its detailed mechanism of celecoxib in the hepatic ischemia reperfusion injury.Objective:1. To observe the effects of different blocking ways to hepatic ischemiareperfusion injury.2. To survey the effects and its functioning mechanism of celecoxibin rats hepatic ischemia reperfusion injury. Methods:1. Select60healthy male SD rates and divide them randomly into2groups (n=30): pure portal vein blocking group (Group A): fully expose hilar, seriouslyseparate hepatic pedicles between left and middle livers, carefully peel off the Glissonsheath and bile ducts on the surfaces, isolate portal veins and hepatic arteries, clip portalvein branches by using of bulldog clamps while keep blood supply of left and middlehepatic arteries and right liver. Hepatic pedicle blocking group (Group B): fully exposehilar, separate portal veins of left and middle livers, hepatic arteries and bile ducts, clipthe whole left and middle hepatic pedicles by using of bulldog clamps. Clipping bothgroups for30min, then take blood samples after1,3,6,12,24hours after the bloodflow recovery to test the concentration of ALT and AST, and take hepatic tissuesspecimen to determine the concentration of MDA and MPO.2. Select30healthy maleSD rates and divide them randomly into5groups (n=6): Group I (control group): lavagephysiological saline after laparotomy blocking portal veins and hepatic arteries; GroupII (sham operated group): laparotomy unblocking portal veins and hepatic arteries andthen make abdominal closure; Group III (Celecoxib group with low dose): lavage10mgcelecoxib after laparotomy blocking portal veins and hepatic arteries; Group IV(Celecoxib group with medium dose): lavage20mg celecoxib after laparotomy blockingportal veins and hepatic arteries; Group V (Celecoxib group with high dose): lavage40mg celecoxib after laparotomy blocking portal veins and hepatic arteries. Clippinghepatic pedicles of each group for6hours before opening, then take blood samples andtest the concentration of ALT and AST in order to determine the injury peak time phaseof hepatic ischemia reperfusion and celecoxib protective effects; and take hepatictissues specimen to determine the concentration of MDA and MPO; observe hepaticischemia reperfusion injury situation by HE dyeing method; and check the expressionlevel of COX-2、STAT3and p-Stat3(pTry705) in hepatic tissues by western blotmethod.Results:1. By monitoring the concentration of ALT, AST, MDA and MPO in rats,we find that compared with hepatic pedicle blocking group (Group B), the ALT andAST concentration in the blood of pure portal vein blocking group (Group A) areobviously lower (P<0.05). At the same time, the MDA and MPO in Group A areevidently lower than that in Group B (P<0.05).2. By monitoring the concentration ofALT, AST, MDA and MPO in rats, we find that compared with Group II (shamoperated group), the ALT and AST concentration in the blood of Group I (control group)are clearly increased (P<0.05). And compared with Group I (control group), the ALT and AST concentration of different dose in celecoxib groups are declined, especiallydistinctively in celecoxib groups (P<0.05). Meanwhile, compared with Group II (shamoperated group), the MDA and MPO concentration in the blood of Group I (controlgroup) are clearly rose (P<0.05). And compared with Group I (control group), the MDAand MPO concentration of different dose in celecoxib groups are dropped (P<0.05),especially noticeably in celecoxib groups. Attentions shall be paid to the most obvioushepatic injury appears after lavage6hours, while celecoxib can change over the hepaticischemia reperfusion injury. It is found that only a little cellular edema occurs and hepaticlobule structures are basically normal in Group II (sham operated group) by using HEdyeing method; while in Group I (control group), hepatic sinusoid are hyperemia andexpanded obviously, and hepatic cells are cellular edema clearly. Cell nucleus are deeplydyed, and a small amount of flakiness can be seen dead; Hepatic cells in celecoxib treatedgroups has partial cellular edema with nucleus deeply dyed, dotted cell dead, portal areaslightly extended, occasionally hyperemia, among which the lower injury of liver cells isGroup IV (Celecoxib group with medium dose). Inspection of Western blot methodsshows the expression level of COX-2, STAT3and p-Stat3(pTry705). Compared withGroup II (sham operated group), the expression level of COX-2and p-Stat3(pTry705) inGroup I (control group) are averagely increased (P<0.05). And compared with Group I(control group), the COX-2and p-Stat3(pTry705) expression level of different dose incelecoxib groups are declined, especially distinctively in celecoxib groups (P<0.05); theexpression level of STAT3has no clearly change in each experimental groups. Attentionsshall be paid to celecoxib protection of the rats hepatic ischemia reperfusion injury arerelated to COX-2and p-Stat3.Conclusions:1. Regional blocking blood supply hepatic lobectomy is a safe operation way thatcan effectively release patients’ hepatic injury during surgeries and beneficial to theliver function recovery after surgeries.2. The hepatic ischemia reperfusion injury in pure portal vein blocking group(Group A) are slighter than that in hepatic pedicle blocking group (Group B). Itsmechanism is possible related to the lipid reroxidation and neutrophils infiltration.3. Celecoxib can reduce the expression levels of ALT, AST, MDA and MPO sothat it can protect the hepatic ischemia reperfusion injury with the best effect in mediumdose (20mg).4. The protection of celecoxib to the hepatic ischemia reperfusion injury may be related to the declined expression level of COX-2and p-Stat3(pTry705). |
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