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Study on Inhibition Effect on the Cyclooxgenase-2 Selective Inhibitor in Hepatic Fibrosis of Mice with Schistosomiasis Japonica

Author: DuJing
Tutor: LiuBaoAn
School: Central South University
Course: Pathology and Pathophysiology
Keywords: Cyclooxgenase-2 selective inhibitor Celecoxib Interferon gamma Schistosoma japonicum hepatic fibrosis
CLC: R96
Type: Master's thesis
Year: 2008
Downloads: 74
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Abstract

Background:Hepatic fibrosis is a pathological process of the extracellular matrix(ECM)depositing abnormally,and characterized by fibroplasia and deposition of collagen at portal areas and in hepatic lobules.Collagen fibersⅠandⅢare tow main compositions.The mechanism is the disharmony between synthesis and degradation of ECM.Liver fibrosis is an important complication of schistosomiasis japonica and can progress into liver cirrhosis finally which is the virulent reason of schistisomiasis japonica.Researches in hepatic fibrosis indicated that many kinds of cytokines controled this process together through autocrine and paracrine.It is also believed that the damage at the stage of liver fibrosis is preventable and reversible. Different medicines exert anti-fibrosis effect through different ways. Interferon-γ,(INF-γ)is produced by activated T cells and NK cells.It is confirmed that INF-γ,has a prominent effect on anti-fibrosis and was recommended by the U.S.Annual Meeting of Liver Disease as the first choice for prevention and treatment of liver fibrosis.However,the application of INF-γ,still has its own disadvantages and there are many factors may impact INF-γ’s drug action.The large does of INF-γ,may induce conspicuous adverse effects.Cyclooxgenase(COX)is the rate-limiting enzyme in conversion of arachidonic acid to prostaglandin(PG).It’s reported that COX have two isoenzymes at least,COX-1 and COX-2.COX-1 exsits in histiocyte cells in gastrointestinal tract、kidney and blood plaques normally.The PG catalyzed by COX-1 is used to maintain the balance of internal environment.COX-2 is known as induced enzyme which is express in small or scarce quantities.Large quantities of COX-2 will be expressed by macrophages and other cells when the body receives the external irritant.At this time,as the mediator of pain,inflammation and fever,the production of PG becomes faster.Conventional NSAIDs have analgesic effect by inhibiting COX-1 and COX-2 simultaneously, which often causes serious side-effects.To solve this probem,the selective inhibitors of COX-2 were invented which had the same effects as NSAIDs,but the side-effects were dramatically decreased. Recent studies reported that COX-2 was a preventive and therapeutic target molecule in inflammation and cancer,especially in digestive tract tumors.And people also found that in liver tissues from virus hepatisis,liver fibrosis and liver cirrhosis patients expressed more COX-2 than normal.Therefore COX-2 was introduced as a new preventive and treatment target in liver fibrosis and cirrhosis.Celecoxib is the first high-performance selective inhibitor of COX-2,which has got the validation from U.S.Food and Drug Administration as the drug to treat rheumatic disease and ostarthritis.The effect of Celecoxib is like the classical NSAIDS,but its side-effects are much less than NSAIDS’s.Some researches have showed that Celecoxib can restrain the disintegration and generation of fibroblastic cells as well as the synthesis of ECM.Therefore we make a hypothesis that Celecoxib has an anti-fibrosis effect in Schistosomiasis Japonica,which remains to be determined.Objective:The present study was to investigate the preventive effect of the cyclooxgenase-2 selective inhibitor celecoxib in hepatic fibrosis caused by schistosoma japonicaMethods:(1)Establish the model of mouse schistosoma japonica hepatic fibrosis.Divide mice into:group A(normal control),group B (INF-γ,dealing group),group C1(celecoxib 10mg/kg.d dealing group), group C2(celecoxib 20mg/kg.d dealing group),group C4(celecoxib 40mg/kg.d dealing group),and group D(infective control);(2)Detect the TP,ALT,AST and HA in serum.(3)Compare hepatic fibrosis degrees and spawn granulomas’ size by mice’s hepatic tissues HE coloretur and MASSON coloretur;(4)Compare expressions of TGF-β1 and a-SMA through immunohistochemical methods;(5)Compare expressions of TGF-β1 mRNA using RT-PCR methods.Results:(1)Celecoxib could make an influence in the mortality of mice:Both celecoxib and INF-γcan decrease mortalities,and the effect of group C2 is more obvious;(2)Celecoxib could create a preventive effect to mice hepatic fibrosis:Both celecoxib and INF-γcould repress the hepatic ponderal growth in hepatic fibrosis of mice with schistosomiasis japonica(P＜0.05).Hepatic weights of group C2 and C4 are lighter than group B(P＜0.05);Celecoxib and INF-γ,can restrain the development of spawn granuloma and diminish collagens deposition in hepatic fibrosis of mice with schistosomiasis japonica (P＜0.05);Both celecoxib and INF-γ,could reduced the expression of TGF-β1 in liver tissues(P＜0.05),and the expression in group C2 and C4 are lower than group C1 and B(P＜0.05);They also decrease the expression of TGF-β1mRNA in hepatic fibrosis of mice with schistosomiasis japonica(P＜0.05);Celecoxib and INF-γ,can reduce a-SMA in liver tissues from hepatic fibrosis of mice with schistosomiasis japonica,and celecoxib has a dose dependent tendency;Celecoxib and INF-γ,can restrain quantities of HA (P＜0.05);(3)Celecoxib can produce influences to the liver function of mice:Group C1 could influence quantities of TP and ALT,whose effect is smaller than group B’s(P＜0.05)Group C2 also could increase the quantity of ALT,and its effect is smaller than B group’s (P＜0.05).But the influence of celecoxib become more serious when the dose increasing.Conclusion:(1)It is suggested that celecoxib significantly prevent hepatic fibrosis of mice with schistosomiasis japonica;(2)The mechanism for celecoxib to prevent hepatic fibrosis is probably associated with controlling the expressions of TGF-β1 and a-SMA.(3) Compare with INF-γ,celecoxib has the analogous effect to the hepatic fibrosis.The harmful effect to the liver function of 10mg/kg.d and 20mg/kg.d of celecoxib is smaller than that of INF-γ.

Study on Inhibition Effect on the Cyclooxgenase-2 Selective Inhibitor in Hepatic Fibrosis of Mice with Schistosomiasis Japonica

Abstract

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