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血紅素加氧酶-1及其產(chǎn)物在肝病中的作用及其機制

2016-02-01 08:31:15戴靈豪伍義行中國計量大學生命科學學院藥學系浙江省生物計量及檢驗檢疫技術重點實驗室浙江杭州310018
中國藥理學與毒理學雜志 2016年2期
關鍵詞:血紅素肝移植抗炎

戴靈豪,伍義行(中國計量大學生命科學學院藥學系,浙江省生物計量及檢驗檢疫技術重點實驗室,浙江杭州 310018)

血紅素加氧酶-1及其產(chǎn)物在肝病中的作用及其機制

戴靈豪,伍義行(中國計量大學生命科學學院藥學系,浙江省生物計量及檢驗檢疫技術重點實驗室,浙江杭州 310018)

血紅素加氧酶(HO)是降解血紅素成為一氧化碳(CO)、鐵離子和膽綠素過程中的限速酶,其亞型HO-1的誘導、超表達或抑制降解可顯著抑制乙肝和丙肝病毒復制,改善肝急/慢性炎癥及纖維化。HO-1及其代謝產(chǎn)物通過抗炎、抗氧化和抗凋亡作用與細胞保護密切相關,能改善多種因素引起的肝損傷,并對缺血再灌注損傷、急/慢性免疫排斥反應及肝移植生存率均有改善作用。HO-1在腫瘤細胞中過表達,抑制HO-1表達能促進肝癌細胞凋亡、減緩肝癌生長及其血管生成,提示它可能是肝癌治療的潛在靶點。本文分析了HO-1及其產(chǎn)物在病毒性肝炎、肝損傷、肝纖維化、肝移植和肝癌中的作用及其機制,旨在闡明HO-1的靶點特性。鑒于HO-1具有顯著的抗病毒、抗炎和保肝作用,且抑制HO-1表達能抑制肝癌生長,故靶向HO-1可能成為臨床治療肝病及新藥研發(fā)的一種新策略。

血紅素加氧酶-1;病毒性肝炎;肝損傷;肝纖維化;肝移植;肝癌

血紅素加氧酶(heme oxygenase,HO)是血紅素代謝的限速酶,催化血紅素氧化降解成一氧化碳(CO)、鐵離子和膽綠素;膽綠素隨后在膽紅素還原酶的作用下轉變?yōu)槟懠t素[1]。血紅素加氧酶存在3種亞型即HO-1,HO-2和HO-3。HO-1(Hsp32)幾乎在每種細胞中均能應激誘導產(chǎn)生[2]。HO-1表達的一個關鍵調(diào)節(jié)元件是Bach-1,它是一種高度保守的亮氨酸拉鏈蛋白,其中包含了血紅素的結合位點[3]。使用小干擾RNA(siRNA)靶向Bach-1 mRNA能明顯降低其mRNA和蛋白水平,并誘導HO-1基因的表達[4]。HO-1的誘導、過表達或抑制其降解能干預急慢性肝炎[5-6]、肝硬化[7]、肝細胞損傷[5]、乙肝病毒(HBV)和丙肝病毒(HCV)的復制[8-11],保護由肝移植[12]或出血/復蘇[13]造成的缺血再灌注損傷。此外,HO-1在多種癌癥包括口腔鱗癌、胰腺癌、肝癌等中過表達[14-16],抑制HO-1的表達或活性能促進體內(nèi)外癌細胞凋亡[16]。HO-2是組成酶,其產(chǎn)物參與神經(jīng)信號的傳遞。HO-3最初是從大鼠大腦中分離得到,并表現(xiàn)出血紅素依賴性細胞功能調(diào)控作用[17]。

HO-1缺陷小鼠致死率高,而存活的缺陷小鼠則發(fā)展成為與貧血相關的氧化損傷、組織損傷和慢性炎癥,同時還出現(xiàn)異常的低血清鐵水平和肝腎組織鐵沉積[18]。此外,HO-1缺陷患者出現(xiàn)持續(xù)性溶血性貧血、血管內(nèi)溶血和凝血功能異常,在腎和肝組織中檢測到鐵沉積[19-20]。顯然,HO-1對維持機體的正常功能具有重要意義,而且HO-1的表達水平與各種肝病的發(fā)生密切相關,通過調(diào)控HO-1的表達水平有可能干預肝病的進程,從而改善并恢復肝的正常功能。因此,本文綜述了HO-1及其產(chǎn)物在病毒性肝炎、肝損傷、肝纖維化、肝移植及肝癌中的作用及其機制,旨在闡明HO-1的潛在靶點特性,以期為肝病的臨床治療及新藥研發(fā)提供一種新的策略和思路。

1 HO-1對病毒性肝炎的影響

HBV和HCV慢性感染是肝進行性炎癥并發(fā)展為肝癌的主要原因[21]。HO-1誘導表達或過量表達能干預HBV[8,22]和HCV[9-11]的復制。采用急性(將含1.3倍HBV基因組的重組腺病毒載體AdHBV注射野生型小鼠)和慢性(HBV轉基因動物)HBV感染模型研究表明,HO-1誘導表達能顯著改善肝損傷且具有顯著的直接的抗病毒效應。通過轉染HBV的肝癌細胞研究顯示,這種抗HBV作用是在轉錄后水平上實現(xiàn)的,由于HO-1降低了核殼蛋白的穩(wěn)定性,從而阻斷cccDNA池的補充,進一步抑制了HBV復制[8]。而且在人肝中大量表達的微RNA (microRNA122,miR-122)能干預HO-1表達,從而促進HBV的復制[22-23]。

有關HCV感染期間HO-1表達的內(nèi)源性調(diào)控作用尚存在爭議,但在HCV復制的肝癌細胞中發(fā)現(xiàn)HO-1表達增加而Bach-1表達減少現(xiàn)象[24]。在表達HCV核心蛋白的細胞系中HO-1表達受到抑制,同時在感染HCV的患者中HO-1水平下調(diào),而未感染HCV肝中HO-1水平上調(diào)[25-26]。還有報道,HCV核心蛋白能干預由血紅素、重金屬和過氧化物誘導的HO-1表達[27]。這些證據(jù)提示,HCV核心蛋白可能負責HCV感染細胞中HO-1表達的調(diào)控。同時,HO-1對HCV復制的影響已通過miRNA研究得到闡明,miR-122可能是HCV RNA復制所需要的成分[28]。通過使用miR-122抑制劑減少HCV RNA復制,而轉染甲基化miR-122則提高HCV復制水平多達2.5倍;miR-122抑制劑還能降低Bach-1水平而增加HO-1 mRNA水平,這表明miR-122對HCV復制影響的可能機制[9]。此外,還有報道,miR-196能下調(diào)HO-1轉錄抑制因子Bach-1水平,從而上調(diào)HO-1的表達[29]。

雖然尚無足夠證據(jù)表明HO-1降解產(chǎn)物具有抑制HBV的作用,但它對HCV復制已確定具有影響。采用HCV復制子細胞系研究表明,CO和鐵離子都不能干預HCV的復制[11],而膽綠素能通過誘導干擾素表達來降低HCV復制介導的氧化應激[11-12]。最近研究表明,膽綠素有抑制HCV非結構蛋白NS3/4A的作用[30],而NS3/4A也是新近開發(fā)的抗HCV藥物特拉匹韋(telaprevir)的一個作用靶點[31]。

2 HO-1對肝損傷及其炎癥的影響

HO-1誘導表達或其降解產(chǎn)物對急性肝炎和敗血癥動物模型顯示了明顯的改善作用[5-6,32-33]。在由脂多糖和D-半乳糖胺誘導的急性肝損傷小鼠模型中,HO-1的誘導減少了細胞因子表達,改善了小鼠肝損傷并延長了其存活時間[5]。HO-1系統(tǒng)還通過增加M2巨噬細胞表型及減少M1巨噬細胞表型、趨化因子和細胞因子表達發(fā)揮其抗大鼠肝炎的作用[34]。對硫代乙酰胺誘導的大鼠肝損傷研究表明,HO-1的抗氧化和抗炎效應是通過減少NO產(chǎn)生實現(xiàn)的[35]。采用大鼠乙醇性肝炎模型研究顯示,脂聯(lián)素(adiponectin)的抗炎作用是通過Kupffer細胞HO-1依賴途徑被介導的[36]。

HO-1催化血紅素降解的產(chǎn)物(CO、膽紅素和游離鐵)均與細胞保護相關,其中CO具有抑制炎癥反應以及促進巨噬細胞抗炎的作用[37]。采用免疫介導的小鼠肝損傷模型研究表明,單用CO并不能干預細胞因子釋放,卻能抑制肝細胞凋亡[5]。而外源性CO能誘導HO-1表達,這說明CO的抗炎作用可能是通過誘導HO-1所介導的。通過乙醇致肝損傷小鼠模型研究顯示,HO-1誘導釋放的CO可能是通過激活P38絲裂原激活蛋白激酶信號通路發(fā)揮其抗氧化和抗炎作用的[38]。雖然HO-1誘導產(chǎn)生的膽綠素并不干預細胞因子釋放,但CO和膽綠素聯(lián)合應用卻抑制如腫瘤壞死因子α(tumor necrosis factor-α,TNF-α)等細胞因子的產(chǎn)生[5]。膽紅素和膽綠素的保護作用主要是基于它們的抗氧化效應,膽紅素在體外對淋巴細胞和粒細胞具有免疫抑制作用,在體內(nèi)接觸抗原后能影響免疫細胞的分化[39]。此外,HO-1誘導的膽紅素能通過膽綠素氧化酶信號通路對抗乙醇致大鼠肝細胞毒性[40]。

HO-1催化血紅素降解的第3種產(chǎn)物鐵離子也具有抗肝炎作用[41]。Kupffer細胞能產(chǎn)生TNF-α和白細胞介素6等細胞因子,而Kupffer細胞在紅細胞吞噬的鐵離子循環(huán)過程中起關鍵作用。增加敗血癥模型中血紅素的攝取量會導致巨噬細胞誘導產(chǎn)生大量HO-1[42]。HO-1能抑制由脂多糖誘導的RAW 264.7巨噬細胞的細胞因子的釋放,說明這可能是一種免疫調(diào)節(jié)作用[43]。此外,將二價亞鐵離子應用于Kupffer細胞,能以一種氧化還原依賴的方式直接激活IκB激酶/NF-κB和TNF-α的啟動子活性,從而增加TNF-α釋放[44]。來源于血紅素的游離鐵離子還能促進Kupffer細胞NF-κB的激活,并表達TNF-α和白細胞介素6等促炎基因[45]。然而,來源于血紅素的鐵離子的抗炎或促炎作用依舊缺乏體內(nèi)實驗證據(jù)。

3 HO-1對肝纖維化的影響

有關HO-1誘導表達對Mdr2ko小鼠的影響研究表明,Mdr2轉運蛋白的缺失會導致膽固醇和磷脂酰膽堿的積累,從而造成慢性炎癥和纖維化[46]。在該模型中HO-1誘導表達的抗炎作用與肝白細胞、巨噬細胞、中性粒細胞、CD3+和Foxp3+T細胞總量的減少有關,同時CD3+/Foxp3+T細胞的比例促使小鼠傾向處于免疫抑制狀態(tài)[46]。肝星狀細胞HO-1誘導表達顯著降低了它們的體內(nèi)外活性,如產(chǎn)生更少的膠原纖維和α-SMA表達[7]。Tsui等[47]將重組腺病毒(rAAV-HO-1)導入到肝星狀細胞中,然后將這些細胞轉入經(jīng)四氯化碳處理的大鼠中,結果顯著減少小結節(jié)型肝硬化、降低肝膠原纖維表達,并抑制肝星狀細胞的增殖能力。此外,在Mdr2ko小鼠體內(nèi)HO-1誘導表達能干預纖維化,甚至表現(xiàn)出纖溶活性[7]。

在肝纖維化大鼠模型中,HO-1誘導能通過增加肝組織過氧化物酶增殖物激活受體γ表達和減少NF-κB表達,實現(xiàn)其對纖維化肝臟的保護作用[48]。研究發(fā)現(xiàn),肝硬化患者Kupffer細胞和肌成纖維細胞HO-1表達出現(xiàn)顯著上調(diào),其中肌成纖維細胞的HO-1誘導表達與纖溶活性密切相關[49]。體外研究顯示,輕度氧化應激和P38蛋白激酶信號通路介導激活了人肝成纖維細胞HO-1的表達[50]。采用膽管結扎誘導大鼠肝硬化的模型研究表明,HO-1抑制劑能通過NF-E2相關因子2/Keap信號通路減少肝的鐵沉積和CO水平,從而改善肝纖維化[51]。

4 HO-1對肝移植的影響

肝移植手術已成為解決終末期肝病患者肝功能恢復的重要治療手段,肝移植的成功與否主要取決于對缺血再灌注損傷和急/慢性移植排斥的處理效果。缺血會導致組織低氧和營養(yǎng)缺乏,從而誘導氧化應激、細胞凋亡、激活非特異性免疫反應和隨后的適應性免疫系統(tǒng)[52]。HO-1能干預氧化應激、細胞凋亡和促炎性免疫應答。肝移植的結果還與捐贈者的HO-1啟動子多態(tài)性相關,高移植生存率存在于HO-1高表達人群[53]。多項研究也表明HO-1過量表達有利于缺血再灌注改善和不同器官的移植[54-55]。在大鼠脂肪肝低溫缺血再灌注損傷模型中,通過CoPP誘導HO-1表達或通過腺病毒介導的基因轉移誘導HO-1過量表達均顯著提高了門靜脈血流量、增加了膽汁分泌和改善了肝損傷。此外,在大鼠肝原位移植中,采用CoPP預處理或直接運用HO-1能使移植受體存活率提高1倍,并能保護肝臟結構、改善肝功能、減少T細胞和巨噬細胞的浸潤[12]。同樣,在其他器官移植中改變HO-1表達水平也能提高移植存活率。

HO-1降解產(chǎn)物對缺血再灌注損傷、急性免疫排斥反應及移植生存率均有積極影響。采用補充CO的血液體外灌注大鼠肝能顯著降低門靜脈阻力、增加膽汁分泌、改善肝功能和肝損傷的病理學改變[56]。據(jù)報道CO介導的細胞保護效應不依賴NO合酶和環(huán)鳥苷酸,而是依賴P38絲裂原活化蛋白激酶[56]。CO的保護效應也可能是通過調(diào)控CO釋放分子來實現(xiàn)的[57]。膽紅素具有免疫抑制能力,能抑制細胞毒T細胞從而干預肝中CD4+T細胞所誘導的炎癥反應,這種抑制作用可能是通過Fas/ CD95-FasL信號轉導通路實現(xiàn)的[58-59]。作為HO-1第三種產(chǎn)物的鐵離子所形成的鐵蛋白也具有改善大鼠肝缺血再灌注損傷及同源受體肝移植的細胞損傷作用,鐵蛋白的體內(nèi)保護效應是與內(nèi)皮細胞和肝細胞的凋亡抑制相關的[60]。

5 HO-1對肝癌的影響

雖然HO-1誘導表達能干預慢性肝炎及纖維化過程,甚至能分解已形成的纖維化,但HO-1在腫瘤細胞中過量表達,似乎表明HO-1是引起癌變的一個因素[7]。事實上,在多種癌癥細胞中HO-1過量表達,如口腔鱗癌[14]、胰腺癌[15]和肝癌[16]等。特別是在口腔鱗癌中HO-1啟動子的多態(tài)性與癌癥發(fā)生率相關,甚至可能作為復發(fā)和存活的預后標志[61]。同樣,在日本女性中高HO-1啟動子活性與增加胃癌風險相關[62]。Lo等[63]鑒定了HO-1啟動子中GT重復序列的長度和胃腺癌風險的關聯(lián)。這些研究表明,HO-1增量表達也許與腫瘤細胞的生存優(yōu)勢相關。抑制HO-1表達或活性在體內(nèi)外均促進肝癌細胞凋亡[16]。采用siRNA下調(diào)HO-1表達導致腫瘤細胞的損傷和凋亡增加,減少細胞增殖,減緩原位肝癌的生長和血管的生成[16]。此外,在其他類型癌癥中,HO-1的抑制能改善放射治療[64]或藥物治療[65]等的治療效果。

HO-1的抗凋亡作用主要是由血紅素降解產(chǎn)物CO實現(xiàn)的[5,65]。研究表明,CO能直接干預通過抗CD95單抗[5]或氧化損傷[66]誘導產(chǎn)生的肝細胞凋亡。雖然HO-1和CO能通過抑制c-Jun N端激酶活性保護原代肝細胞對抗超氧陰離子誘導的凋亡,但肝中CO依賴的抗凋亡下游信號還未完全闡明[66]。HO-1的第二個產(chǎn)物膽綠素尚無有關抗肝細胞凋亡作用的報道,而由HO-1的第3個產(chǎn)物鐵離子誘導的鐵蛋白能保護由多種刺激誘導的內(nèi)皮細胞凋亡[60]。由重組腺病毒介導的鐵蛋白重鏈基因的過度表達也能保護大鼠肝的缺血再灌注損傷,且能防止移植到同源受體的血管內(nèi)皮細胞和肝細胞發(fā)生凋亡[60]。最近報道HO-1通過抑制TNF/TNFR1介導的凋亡信號、調(diào)節(jié)凋亡誘導復合物的形成和線粒體TNFR1的易位來實現(xiàn)其抗凋亡的細胞保護效應[67]。上述研究表明,HO-1或CO對外在因素誘導的凋亡損傷可能是一種有用的保護工具,但如果在腫瘤細胞中大量存在,它可能是肝癌治療的一個潛在靶點。

6 展望

HO-1作為一種保護性酶,其重要性在HO-1缺陷患者中已得到證實,而HO-1表達的調(diào)控可能成為臨床上肝炎和肝癌治療的一種新策略。一方面,由于HO-1具有顯著的抗病毒、抗炎、抗氧化、抗凋亡及保肝作用,故HO-1的誘導或超表達可用于病毒性肝炎(包括乙肝和丙肝)[8-9]、各種原因引起的肝損傷以及肝纖維化的治療[5,48],還可改善缺血再灌注損傷、減少急/慢性免疫排斥反應及提高肝移植生存率[53-55]。但目前存在的問題是,雖然HO-1能被多種刺激劑所誘導,但仍缺乏有效的HO-1特異性誘導劑;而在體外或動物實驗中使用的HO-1誘導劑(如CoPP)并不適合直接用于患者。為解決這個問題,有學者試圖使用miR-196[29]、miR-122拮抗劑[9]、蛋白轉導域-HO-1蛋白(PTD-HO-1)[68]、或通過siRNA直接沉默HO-1轉錄抑制因子Bach-1來提高HO-1表達[4]。而三羥基三甲基戊二酸單酰輔酶A (HMG輔酶A)還原酶抑制劑具有在多種組織中誘導HO-1表達的作用[69],但臨床上這些HO-1誘導劑的應用(如治療HCV)仍受到爭議主要受限于其療效的差異性[70-71]。另外,本課題組探討了HBV感染與HO-1表達的動態(tài)相關性,也證實了HO-1誘導表達與HBV感染的直接關系,驗證了HO-1對HBV復制的顯著抑制作用[72-73]。顯然,今后的方向仍然是尋找肝特異性安全有效的HO-1誘導劑,包括天然和合成的小分子以及生物制品。

另一方面,由于HO-1被發(fā)現(xiàn)在多種腫瘤細胞中過量表達(如肝癌[16]、口腔鱗癌[14]、胰腺癌[15]、腎癌[74]和前列腺癌[75]等),而抑制HO-1表達或活性能促進肝癌細胞凋亡,減少細胞增殖,減緩肝癌生長及其血管生成[16],提示它可能成為肝癌潛在的治療靶點,故下調(diào)HO-1表達的選擇性HO-1抑制劑可能成為包括肝癌在內(nèi)的多種腫瘤治療的新方向。例如,小分子選擇性HO-1抑制劑OB-24在體內(nèi)外被證明具有廣譜抗腫瘤活性,尤其是能顯著抑制前列腺癌細胞增殖和腫瘤生長,而且還與腫瘤化療藥物具有協(xié)同作用[65,76]。因此,新型小分子選擇性HO-1抑制劑仍有必要繼續(xù)深入研究。綜上所述,肝特異性HO-1誘導劑和小分子選擇性HO-1抑制劑分別在肝炎和肝癌治療中具有重要意義和巨大潛力。

[1] Maines MD.Heme oxygenase:function,multiplicity,regulatory mechanisms,and clinical applications [J].FASEB J,1988,2(10):2557-2568.

[2] Elbirt KK, Bonkovsky HL.Hemeoxygenase:recent advances in understanding its regulation and role[J].Proc Assoc Am Physicians,1999,111(5):438-447.

[3] Sun J,Hoshino H,Takaku K,Nakajima O,Muto A,Suzuki H,et al.Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene [J].EMBO J,2002,21(19):5216-5224.

[4] Shan Y,Lambrecht RW,Ghaziani T,Donohue SE,Bonkovsky HL.Role of Bach-1 in regulation of heme oxygenase-1 in human liver cells:insights from studies with small interfering RNAs[J].J Biol Chem,2004,279(50):51769-51774.

[5] SassG, SeyfriedS,ParreiraSoaresM,Yamashita K,Kaczmarek E,Neuhuber WL,et al. CooperativeeffectofbiliverdinandCarbon monoxide on survival of mice in immune-mediated liver injury[J].Hepatology,2004,40(5):1128-1135.

[6] Sass G,Soares MC,Yamashita K,Seyfried S,Zimmermann WH,Eschenhagen T,et al.Heme oxygenase-1 and its reaction product,carbon monoxide,prevent inflammation-related apoptotic liver damage in mice[J].Hepatology,2003,38 (4):909-918.

[7] Barikbin R, Neureiter D, Wirth J, Erhardt A,Schwinge D,Kluwe J,et al.Induction of heme oxygenase 1 prevents progression of liver fibrosis in Mdr2 knockout mice[J].Hepatology,2012,55 (2):553-562.

[8]Protzer U,Seyfried S,Quasdorff M,Sass G,Svorcova M,Webb D,et al.Antiviral activity and hepatoprotection by heme oxygenase-1 in hepatitis B virus infection[J].Gastroenterology,2007,133(4):1156-1165.

[9] Shan Y,Zheng J,Lambrecht RW,Bonkovsky HL. Reciprocal effects of micro-RNA-122 on expression of heme oxygenase-1 and hepatitis C virus genes inhumanhepatocytes[J].Gastroenterology,2007,133(4):1166-1174.

[10] Zhu Z,Wilson AT, Mathahs MM,Wen F,Brown KE,Luxon BA,et al.Heme oxygenase-1 suppresseshepatitisCvirusreplicationandincreases resistance of hepatocytes to oxidant injury[J].Hepatology,2008,48(5):1430-1439.

[11]LehmannE,El-TantawyWH,OckerM,Bartenschlager R,Lohmann V,Hashemolhosseini S,et al.The heme oxygenase 1 product biliverdin interferes with hepatitis C virus replication by increasing antiviral interferon response [J].Hepatology,2010,51(2):398-404.

[12] Amersi F,Buelow R,Kato H,Ke B,Coito AJ,Shen XD,et al.Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury[J].J Clin Invest,1999,104(11):1631-1639.

[13] Rensing H, Bauer I, Datene V, P?tau C,Pannen BH,Bauer M.Differential expression pattern of heme oxygenase-1/heat shock protein 32 and nitric oxide synthase-Ⅱ and their impact on liver injury in a rat model of hemorrhage and resuscitation[J].Crit Care Med,1999,27(12):2766-2775.

[14] Lee J,Lee SK,Lee BU,Lee HJ,Cho NP,Yoon JH,et al.Upregulation of heme oxygenase-1 in oral epithelial dysplasias[J].Int J Oral Maxillofac Surg,2008,37(3):287-292.

[15] NuhnP,KünzliBM,HennigR,Mitkus T,Ramanauskas T,Nobiling R,et al.Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo[J].Mol Cancer,2009,8:37.

[16] Sass G,Leukel P,Schmitz V,Raskopf E,Ocker M,Neureiter D,et al.Inhibition of heme oxygenase 1 expression by small interfering RNA decreases orthotopic tumor growth in livers of mice[J].Int J Cancer,2008,123(6):1269-1277.

[17] Mccoubrey WK,Huang TJ,Maines MD.Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3[J]. Eur J Biochem,1997,247(2):725-732.

[18] Poss KD,Tonegawa S.Hemeoxygenase 1is required for mammalian iron reutilization[J].Proc Natl Acad Sci USA,1997,94(20):10919-10924.

[19] Yachie A,Niida Y,Wada T,Igarashi N,Kaneda H,Toma T,et al.Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency[J].J Clin Invest,1999,103(1):129-135.

[20] Kawashima A,Oda Y,Yachie A,Koizumi S,Nakanishi I.Heme oxygenase-1 deficiency:the first autopsy case[J].Hum Pathol,2002,33(1):125-130.

[21] El-Serag HB,Rudolph KL.Hepatocellular carcinoma:epidemiology and molecular carcinogenesis[J]. Gastroenterology,2007,132(7):2557-2576.

[22] Qiu L,F(xiàn)an H,Jin W,Zhao B,Wang Y,Ju Y,et al.miR-122-induced down-regulation of HO-1 negatively affects miR-122-mediated suppression of HBV[J].Biochem Biophys Res Commun,2010,398(4):771-777.

[23] Chang J,Nicolas E,Marks D,Sander C,Lerro A,Buendia MA,et al.miR-122,a mammalian liverspecific microRNA,is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1[J].RNA Biol,2004,1(2):106-113.

[24] Ghaziani T,Shan Y,Lambrecht RW,Donohue SE,Pietschmann T,Bartenschlager R,et al.HCV proteins increase expression of heme oxygenase-1 (HO-1)anddecreaseexpressionofBach1inhuman hepatoma cells[J].J Hepatol,2006,45(1):5-12.

[25] Abdalla MY,Mathahs MM,Ahmad IM.Reduced heme oxygenase-1 expression in steatotic livers infected with hepatitis C virus[J].Eur J Intern Med,2012,23(7):649-655.

[26]Abdalla MY,Britigan BE,Wen F,Icardi M,Mccormick ML,Labrecque DR,et al.Down-regulation of heme oxygenase-1 by hepatitis C virus infection in vivo and by the in vitro expression of hepatitis C core protein[J].J Infect Dis,2004,190(6):1109-1118.

[27]Wen F,Brown KE,Britigan BE,Schmidt WN. Hepatitis C core protein inhibits induction of heme oxygenase-1 and sensitizes hepatocytes to cytotoxicity[J].Cell Biol Toxicol,2008,24(2):175-188.

[28] Jopling CL,Yi M,Lancaster AM,Lemon SM,Sarnow P.Modulation of hepatitis C virus RNA abundancebyaliver-specificmicroRNA[J]. Science,2005,309(5740):1577-1581.

[29] Hou W, Tian Q, Zheng J,Bonkovsky HL. MicroRNA-196repressesBach1proteinand hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins [J].Hepatology,2010,51(5):1494-1504.

[30]Zhu Z, Wilson AT, Luxon BA,Brown KE,Mathahs MM,Bandyopadhyay S,et al.Biliverdin inhibits hepatitis C virus nonstructural 3/4A protease activity:mechanism for the antiviral effects of heme oxygenase?[J].Hepatology,2010,52(6):1897-1905.

[31] Lin C,Kwong AD,Perni RB.Discovery and development of VX-950,a novel,covalent,and reversible inhibitor of hepatitis C virus NS3.4Aserine protease[J].Infect Disord Drug Targets,2006,6(1):3-16.

[32] Tsoyi K,Lee TY,Lee YS,Kim HJ,Seo HG,Lee JH,et al.Heme-oxygenase-1 induction and Carbon monoxide-releasing molecule inhibit lipopolysaccharide(LPS)-inducedhigh-mobilitygroup box 1 release in vitro and improve survival of mice in LPS-and cecal ligation and puncture-induced sepsis model in vivo[J].Mol Pharmacol,2009,76(1):173-182.

[33] Chung SW,Liu X,Macias AA,Baron RM,Perrella MA.Heme oxygenase-1-derived Carbon monoxide enhances the host defense response to microbial sepsis in mice[J].J Clin Invest,2008,118(1):239-247.

[34] Salley TN,Mishra M,Tiwari S,Jadhav A,Ndisang JF.The heme oxygenase system rescues hepatic deterioration in the condition of obesity co-morbid with type-2 diabetes[J].PLoS One,2013,8 (11):e79270.

[35] Develi-Is S,Bekpinar S,Kalaz EB,Evran B,Unlucerci Y,Gulluoglu M,et al.The protection by heme oxygenase-1 induction against thioacetamide-induced liver toxicity is associatedwith changes in arginine and asymmetric dimethylarginine[J].Cell Biochem Funct,2013,31(2):122-128.

[36] Mandal P,Park PH,Mcmullen MR,Pratt BT,Nagy LE.The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependentpathwayinratKupffercells[J]. Hepatology,2010,51(4):1420-1429.

[37] Otterbein LE,Soares MP,Yamashita K,Bach FH. Heme oxygenase-1:unleashing the protective properties of heme[J].Trends Immunol,2003,24(8):449-455.

[38] Li Y,Gao C,Shi Y,Tang Y,Liu L,Xiong T,et al. Carbonmonoxidealleviatesethanol-induced oxidativedamageandinflammatorystress throughactivatingp38MAPKpathway[J]. Toxicol Appl Pharmacol,2013,273(1):53-58.

[39] Síma P,Malá J,Miler I,Hodr R,Truxová E.The suppressive effect of continuous infusion of bilirubin on the immune response in mice[J].Folia Microbiol (Praha),1980,25(6):483-490.

[40] Jie Q,Tang Y,Deng Y,Li Y,Shi Y,Gao C,et al.Bilirubin participates in protecting of heme oxygenase-1 induction by quercetin against ethanol hepatotoxicityinculturedrathepatocytes[J]. Alcohol,2013,47(2):141-148.

[41] Immenschuh S,Baumgart-Vogt E,Mueller S. Heme oxygenase-1 and iron in liver inflammation:a complex alliance[J].Curr Drug Targets,2010,11(12):1541-1550.

[42] Schaer DJ,Schaer CA,Schoedon G,Imhof A,Kurrer MO.Hemophagocytic macrophages constitute amajorcompartmentofhemeoxygenase expression in sepsis[J].Eur J Haematol,2006,77(5):432-436.

[43] Li QF,Zhu YS,Jiang H,Xu H,Sun Y.Heme oxygenase-1 mediates the anti-inflammatory effect of isoflurane preconditioning in LPS-stimulated macrophages[J].Acta Pharmacol Sin,2009,30 (2):228-234.

[44] She H,Xiong S,Lin M,Zandi E,Giulivi C,Tsukamoto H.IronactivatesNF-kappaB in Kupffer cells[J].Am J Physiol Gastrointest Liver Physiol,2002,283(3):G719-G726.

[45] Tsukamoto H,Lin M,Ohata M,Giulivi C,F(xiàn)rench SW,Brittenham G.Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury[J].Am J Physiol,1999,277(6 Pt 1):G1240-G1250.

[46] Mauad TH,Van Nieuwkerk CM,Dingemans KP,Smit JJ,Schinkel AH,Notenboom RG,et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene.A novel animal model for studies of nonsuppurative inflammatory cholangitis andhepatocarcinogenesis[J].AmJPathol,1994,145(5):1237-1245.

[47] Tsui TY,Lau CK,Ma J,Wu X,Wang YQ,F(xiàn)arkas S,et al.rAAV-mediated stable expression of heme oxygenase-1 in stellatecells:anew approach to attenuate liver fibrosis in rats[J]. Hepatology,2005,42(2):335-342.

[48] Yang H,Zhao LF,Zhao ZF,Wang Y,Zhao JJ,Zhang L.Heme oxygenase-1 prevents liver fibrosis in rats by regulating the expression of PPARγ and NF-κB[J].World J Gastroenterol,2012,18 (14):1680-1688.

[49]Li L,Grenard P,Nhieu JT,Julien B,Mallat A,Habib A,et al.Heme oxygenase-1 is an antifibrogenic protein in human hepatic myofibroblasts [J].Gastroenterology,2003,125(2):460-469.

[50] Li L,Julien B,Grenard P, Teixeira-Clerc F,Mallat A,Lotersztajn S.Molecular mechanisms regulatingtheantifibrogenicproteinhemeoxygenase-1 in human hepatic myofibroblasts[J]. J Hepatol,2004,41(3):407-413.

[51] Wang QM,Du JL,Duan ZJ,Guo SB,Sun XY,Liu Z.Inhibiting heme oxygenase-1 attenuates ratliver fibrosis by removing iron accumulation[J]. World J Gastroenterol,2013,19(19):2921-2934.

[52] ?llinger R,Pratschke J.Role of heme oxygenase-1 in transplantation[J].Transpl Int,2010,23(11):1071-1081.

[53] Buis CI,Van Der Steege G,Visser DS,Nolte IM,Hepkema BG,Nijsten M,et al.Heme oxygenase-1 genotype of the donor is associated with graft survivalafterlivertransplantation[J].AmJ Transplant,2008,8(2):377-385.

[54] Katori M,Buelow R,Ke B,Ma J,Coito AJ,Iyer S,et al.Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway[J].Transplantation,2002,73(2):287-292.

[55] Kato H,Amersi F,Buelow R,Melinek J,Coito AJ,Ke B,et al.Heme oxygenase-1 overexpression protects rat livers from ischemia/reperfusion injury withextendedcoldpreservation[J].AmJ Transplant,2001,1(2):121-128.

[56] Amersi F,Shen XD,Anselmo D,Melinek J,Iyer S,Southard DJ,et al.Ex vivo exposure to Carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway[J]. Hepatology,2002,35(4):815-823.

[57] Clark JE,Naughton P,Shurey S,Green CJ,Johnson TR,Mann BE,et al.Cardioprotective actions by a water-soluble Carbon monoxidereleasingmolecule[J].CircRes,2003,93(2):e2-e8.

[58] StockerR,YamamotoY,McdonaghAF,GlazerAN,Ames BN.Bilirubin is an antioxidant of possible physiological importance[J].Science,1987,235 (4792):1043-1046.

[59] Mcdaid J,Yamashita K,Chora A,Ollinger R,Strom TB,Li XC,et al.Heme oxygenase-1 modulates the allo-immune response by promoting activation-inducedcelldeathofTcells[J]. FASEB J,2005,19(3):458-460.

[60] Berberat PO,Katori M,Kaczmarek E,Anselmo D,Lassman C,Ke B,et al.Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury[J].FASEB J,2003,17(12):1724-1726.

[61] Vashist YK,Uzungolu G,Kutup A,Gebauer F,Koenig A,Deutsch L,et al.Heme oxygenase-1 germ line GTn promoter polymorphism is an Independent prognosticator of tumor recurrence and survival in pancreatic cancer[J].J Surg Oncol,2011,104(3):305-311.

[62]Sawa T,Mounawar M,Tatemichi M,Gilibert I, Katoh T,Ohshima H.Increased risk of gastric cancer in Japanese subjects is associated with microsatellitepolymorphismsintheheme oxygenase-1 and the inducible nitric oxide synthase gene promoters[J].Cancer Lett,2008,269(1):78-84.

[63]Lo SS,Lin SC,Wu CW,Chen JH,Yeh WI,Chung MY, et al.Heme oxygenase-1 gene promoter polymorphism is associated with risk of gastricadenocarcinomaandlymphovascular tumor invasion[J].Ann Surg Oncol,2007,14 (8):2250-2256.

[64] Zhang W,Qiao T,Zha L.Inhibition of heme oxygenase-1 enhances the radiosensitivity in human nonsmall cell lung cancer a549 cells[J].Cancer Biother Radiopharm,2011,26(5):639-645.

[65] Alaoui-Jamali MA,Bismar TA,Gupta A,Szarek WA,Su J,Song W,et al.A novel experimental heme oxygenase-1-targeted therapy for hormonerefractoryprostatecancer[J].CancerRes,2009,69(20):8017-8024.

[66] CondeDL, VrenkenTE, HannivoortRA,Buist-Homan M,Havinga R,Slebos DJ,et al. Carbon monoxide blocks oxidative stress-induced hepatocyte apoptosis via inhibition of the p54 JNK isoform[J].Free Radic Biol Med,2008,44(7):1323-1333.

[67]Kim SJ,Eum HA,Billiar TR,Lee SM.Role of heme oxygenase 1 in TNF/TNF receptor-mediated apoptosis after hepatic ischemia/reperfusion in rats[J].Shock,2013,39(4):380-388.

[68] Ogawa T,H?nggi D,Steiger HJ.Treatment of experimental cerebral vasospasm by protein transduction of heme oxygenase 1(HO-1)conjugated to a residue of 11 arginines[J].Acta Neurochir Suppl,2011,112:111-113.

[69] Chen JC,Huang KC, Lin WW.HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages viaERK,p38MAPKandproteinkinaseG pathways[J].Cell Signal,2006,18(1):32-39.

[70] O′leary JG,Chan JL,McMahon CM,Chung RT. Atorvastatindoesnotexhibitantiviralactivity against HCV at conventional doses:a pilot clinical trial[J].Hepatology,2007,45(4):895-898.

[71] Milazzo L,Caramma I,Mazzali C,Cesari M,Olivetti M,Galli M,et al.Fluvastatin as an adjuvant to pegylated interferon and ribavirin in HIV/hepatitis C virus genotype 1 co-infected patients:an openlabel randomized controlled study[J].J AntimicrobChemother,2010,65(4):735-740.

[72] Shen YM,Zhang HL,Wu YH,Yu XP,Hu HJ,Dai LH.Dynamic correlation between induction of the expression of heme oxygenase-1 and hepatitis B viral replication[J].Mol Med Rep,2015,11 (6):4706-4712.

[73] Wu YH,Hao BJ,Cao HC,Xu W,Li YJ,Li LJ. Anti-hepatitis B virus effect and possible mechanism of action of 3,4-o-dicaffeoylquinic acid in vitro and in vivo[J].Evid Based Complement Alternat Med,2012:356806.

[74] GoodmanAI, Choudhury M, Da Silva JL,Schwartzman ML,Abraham NG.Overexpression of the heme oxygenase gene in renal cell carcinoma [J].Proc Soc Exp Biol Med,1997,214(1):54-61.

[75]Maines MD,Abrahamsson PA.Expression of heme oxygenase-1(HSP32)in human prostate:normal,hyperplastic,and tumor tissue distribution [J].Urology,1996,47(5):727-733.

[76]Alaoui-Jamali MA,Szarek WA,Nakatsu KA,Gupta A,Schipper HM.OB-24,a novel selective and potent HO-1 inhibitor,induces a wide spectrum anti-tumor activity in vitro and in vivo and synergizes with chemotherapy drugs[J].Mol Cancer Ther,2007,6(11 Suppl):C82-C82.

Effect and mechanism of heme oxygenase-1 and its reaction products of heme degradation on liver diseases

DAI Ling-hao,WU Yi-hang
(Zhejiang Provincial Key Laboratory of Biometrology and Inspection&Quarantine,Department of Pharmacy,College of Life Sciences,China Jiliang University,Hangzhou 310018,China)

Heme oxygenases(HO)are rate-limiting enzymes which degrade heme into carbon monoxide,biliverdin and free iron.HO-1 is the inducible form of HO.Induction and over-expression of HO-1 or inhibition of HO-1 degradation have been shown to interfere with replication of hepatitis B and C viruses,acute and chronic liver inflammation,and progression to fibrosis.HO-1 as well as its reaction products of heme degradation has been linked to cytoprotection by its anti-inflammatory,antioxidative and anti-apoptotic effects,displayed a broad range of protective effects against hepatic damage,and showed beneficial effects on ischemia-reperfusion injury,acute/chronic graft rejection and graft survival rate in liver transplantation.However,HO-1 has been found to be over-expressed in tumor cells.Inhibition of HO-1 expression can promote tumor cell apoptosis,decrease growth of HCC and reduce angiogenesis,suggesting that HO-1 is a potential target in the treatment of hepatic cancer.To validate the target property of HO-1,this review analyzed the effects and mechanism of action of HO-1 and its products in viral hepatitis,liver injury,hepatic fibrosis,liver transplantation and hepatocellular carcinoma.Given HO-1′s marked anti-viral,anti-inflammatory and hepatoprotective properties,the inhibitory effect of its downmodulation on hepatic cancer and the strategy to target HO-1 may promise new areas in both drug development and clinical therapy of liver diseases.

heme oxygenase-1;viral hepatitis;liver injury;hepatic fibrosis;liver transplantation;hepatocellular carcinoma

The project supported by Zhejiang Prooincial Natural Science Foundation of China(LY14H310010);and Scientific Research Foundation for Key Project of Chinese Ministry of Education(212073)

WU Yi-hang,E-mail:yihangwu@126.com,Tel:(0571)86875676

R963

A

1000-3002-(2016)02-0165-08

10.3867/j.issn.1000-3002.2016.02.012

2015-02-15接受日期:2015-11-23)

(本文編輯:齊春會)

浙江省自然科學基金(LY14H310010);教育部科技研究重點項目(212073)

戴靈豪,碩士研究生,主要從事肝臟藥理學研究;伍義行,醫(yī)學博士,教授,主要從事肝臟藥理學與抗肝炎藥物研究。

伍義行,E-mail:yihangwu@126.com;Tel:(0571)86875676

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