孫 思 , 陳玉玲, 左麗娜 , 張文輝 , 喬月華
(1徐州市中心醫(yī)院呼吸內(nèi)科,江蘇 徐州 221009; 2徐州醫(yī)科大學(xué)附屬醫(yī)院呼吸內(nèi)科, 江蘇 徐州 221004)
辛伐他汀對(duì)小鼠巨細(xì)胞病毒肺炎Toll樣受體2表達(dá)的影響*
孫 思1, 陳玉玲2△, 左麗娜2, 張文輝2, 喬月華2
(1徐州市中心醫(yī)院呼吸內(nèi)科,江蘇 徐州 221009;2徐州醫(yī)科大學(xué)附屬醫(yī)院呼吸內(nèi)科, 江蘇 徐州 221004)
目的觀察辛伐他汀對(duì)小鼠巨細(xì)胞病毒(MCMV)肺炎小鼠肺組織Toll樣受體2(Toll-like receptor 2, TLR-2)、干擾素γ(IFN-γ)和單核細(xì)胞趨化蛋白1(MCP-1)表達(dá)的影響,并探討辛伐他汀干預(yù)MCMV肺炎的可能機(jī)制。方法將40只6~8周齡BALB/c小鼠隨機(jī)分成5組:正常對(duì)照(NC)組、MCMV感染組和辛伐他汀干預(yù)(SMV1、SMV2和SMV3)組。SMV1、SMV2和SMV3組分別在腹腔注射MCMV前7 d、與MCMV同時(shí)和MCMV感染后3 d給予辛伐他汀(50 mg·kg-1·d-1,均連續(xù)給藥7 d)灌胃,NC組及MCMV組分別予以同體積的生理鹽水灌胃。HE染色觀察小鼠肺組織的病理改變,real-time PCR檢測(cè)MCMV DNA的變化,免疫組化和Western blot檢測(cè)肺組織中TLR-2的表達(dá),ELISA檢測(cè)肺組織中IFN-γ和MCP-1的變化。結(jié)果與NC組相比,MCMV組肺組織病理染色顯示肺泡間質(zhì)水腫,肺泡壁增寬,內(nèi)可見大量炎性細(xì)胞浸潤(rùn);肺組織中TLR-2的表達(dá)增加,MCMV DNA含量升高,肺組織中炎癥因子IFN-γ和MCP-1明顯增多(P<0.05)。辛伐他汀干預(yù)后,與MCMV組相比,肺組織病理改變較前減輕,TLR-2的表達(dá)下降(P<0.05),MCMV DNA 含量降低(P<0.05),炎性因子IFN-γ和MCP-1明顯下降(P<0.05),且SMV1組TLR-2的表達(dá)量及MCMV DNA含量下降較SMV2和SMV3組更明顯(P<0.05),而SMV2和SMV3兩組相比差異無(wú)統(tǒng)計(jì)學(xué)顯著性。結(jié)論辛伐他汀干預(yù)通過(guò)下調(diào)TLR-2信號(hào)通路而降低TLR-2的表達(dá),減少IFN-γ和MCP-1的分泌,并抑制MCMV DNA的復(fù)制,從而使肺組織的病理?yè)p害得以減輕;且提前給予辛伐他汀干預(yù)對(duì)預(yù)防MCMV的感染及減輕炎癥反應(yīng)具有重要作用。
辛伐他?。?巨細(xì)胞病毒; Toll樣受體2; 干擾素γ; 單核細(xì)胞趨化蛋白1
巨細(xì)胞病毒(cytomegalovirus,CMV)是一種普遍存在的雙鏈DNA病毒,其通常呈隱性感染,多數(shù)感染者無(wú)臨床癥狀,但在一定條件下可以侵襲多個(gè)器官和系統(tǒng)產(chǎn)生嚴(yán)重疾病。數(shù)十年來(lái),預(yù)防CMV感染的藥物不僅有限,而且結(jié)果往往不能令人滿意,因此,迫切需要一種新的更加安全有效的藥物以預(yù)防CMV感染、阻斷炎癥反應(yīng)的通路。已有研究發(fā)現(xiàn),辛伐他汀(simvastatin,SMV),即3-羥基-3-甲基戊二酰輔酶A還原酶抑制劑,除了能有效降低膽固醇水平及減少心血管的發(fā)病,同時(shí)似乎也發(fā)揮一些“多效”作用,尤其在抗炎方面的作用更為突出[1]。既往研究表明,Toll樣受體(Toll-like receptors,TLRs)可能參與辛伐他汀的抗炎過(guò)程[2],而且CMV致使炎癥反應(yīng)的機(jī)制之一可能主要通過(guò)TLR-2-MyD88依賴性途徑介導(dǎo)炎癥反應(yīng)[3-4]。同時(shí)Niessner 等[2]研究發(fā)現(xiàn),辛伐他汀可能抑制TLR-2的表達(dá),導(dǎo)致TLR信號(hào)通路下調(diào),致使下游的細(xì)胞因子、趨化因子分泌減少。此外,抑制TLRs信號(hào)通路,能減少CMV的激活[2]。本實(shí)驗(yàn)旨在探討辛伐他汀對(duì)TLR-2介導(dǎo)的信號(hào)通路和小鼠CMV(mouse CMV, MCMV) DNA復(fù)制的影響,驗(yàn)證其能否成為一種新的預(yù)防CMV感染及減輕炎癥反應(yīng)的藥物。
1動(dòng)物與試劑
6~8周齡SPF級(jí)BALB/c小鼠40只,雄性,購(gòu)自徐州醫(yī)學(xué)院實(shí)驗(yàn)動(dòng)物中心。動(dòng)物飼養(yǎng)于獨(dú)立送風(fēng)隔離籠具系統(tǒng)內(nèi),等級(jí)為屏障系統(tǒng)。小鼠3T3細(xì)胞和MCMV Smith株均由山東省醫(yī)學(xué)科學(xué)院微生物研究所提供。小鼠3T3細(xì)胞按常規(guī)方法培養(yǎng)傳代,病毒致半數(shù)細(xì)胞感染量=108.31/L。辛伐他汀購(gòu)自杭州默沙東有限公司;ELISA試劑盒購(gòu)自上海依科賽生物制品有限公司。
2方法
2.1實(shí)驗(yàn)動(dòng)物分組及模型建立 將40只6~8周齡小鼠隨機(jī)均分成5組,即正常對(duì)照(normal control,NC)組、MCMV感染(MCMV)組和辛伐他汀干預(yù)組(SMV1、SMV2和SMV3組),每組8只。以第1次注射環(huán)磷酰胺為第0天,MCMV、SMV1、SMV2和SMV3組均于第0、1、2天腹腔注射環(huán)磷酰胺(80 mg/kg),第2天注射環(huán)磷酰胺后1 h,MCMV組和SMV干預(yù)組的小鼠每只腹腔注射MCMV株懸液0.8 mL。SMV1組、SMV2組和SMV3組的動(dòng)物分別在腹腔注射MCMV前7 d、同時(shí)和后3 d給予辛伐他汀灌胃(均連續(xù)給藥7 d, 50 mg·kg-1·d-1)。NC組及MCMV組分別予以同體積的生理鹽水灌胃。在此期間觀察小鼠的一般情況,如活動(dòng)、飲水、有無(wú)聳毛、毛發(fā)稀疏等情況。給藥結(jié)束后取小鼠肺組織行HE染色、免疫組化、real-time PCR和Western blot進(jìn)行檢測(cè)。
2.2免疫組化法檢測(cè)TLR-2的表達(dá) 石蠟切片常規(guī)脫蠟、抗原修復(fù)及山羊血清封閉,加TLR-2抗體(1∶500稀釋)4 ℃孵育過(guò)夜,再加生物素標(biāo)記Ⅱ抗孵育,DAB染色。胞膜出現(xiàn)棕黃色顆粒為陽(yáng)性表達(dá)。用Image-Pro Plus 6.0圖像分析軟件采集。每個(gè)指標(biāo)選取5個(gè)不同切面,取平均值進(jìn)行統(tǒng)計(jì)。
2.3Western blot檢測(cè)TLR-2 取肺組織100 mg,提取總蛋白,依次經(jīng)配膠、電泳、轉(zhuǎn)膜、封閉后,孵育TLR-2的Ⅰ抗抗體過(guò)夜,洗膜后加入熒光 II 抗室溫孵育2 h,ECL發(fā)光液顯色后用ImageJ軟件分析條帶的灰度。
2.4Real-time PCR法測(cè)肺組織中MCMV DNA含量 通過(guò)DNA試劑盒從肺組織中提取MCMV DNA,將各組標(biāo)本的DNA濃度進(jìn)行標(biāo)準(zhǔn)化,根據(jù)MCMV DNA的量和ddH2O的量的比例,計(jì)算各組DNA的量。上游引物為5’-TCAGCCATCAACTCTGCTACCAAC-3’,下游引物為5’-ATCTGAAACAGCCGTATATCATCTTG-3’。反應(yīng)條件: 94 ℃ 3 min; 94 ℃ 30 s, 48 ℃ 30 s, 72 ℃ 20 s, 循環(huán)40次; 72 ℃ 10 min; 4 ℃ 冷卻。反應(yīng)完成后,進(jìn)行定量分析,根據(jù)預(yù)值調(diào)整基線,讀出結(jié)果。實(shí)驗(yàn)結(jié)果按照2-ΔΔCt方法處理數(shù)據(jù)。
2.5ELISA檢測(cè)肺組織干擾素γ(interferon-γ,IFN-γ)和單核細(xì)胞趨化蛋白1(monocyte chemoattractant protein-1,MCP-1)的含量 嚴(yán)格按照試劑盒說(shuō)明書操作,酶聯(lián)免疫檢測(cè)儀測(cè)定450 nm處吸光度值,繪制標(biāo)準(zhǔn)曲線,計(jì)算樣本結(jié)果。
3統(tǒng)計(jì)學(xué)處理
采用SPSS 16.0 統(tǒng)計(jì)軟件進(jìn)行數(shù)據(jù)分析,所有數(shù)據(jù)均采用均數(shù)±標(biāo)準(zhǔn)差(mean±SD)表示,多組間均數(shù)比較采用單因素方差分析(one-way ANOVA),組間兩兩比較用SNK-q檢驗(yàn)。以P<0.05 為差異有統(tǒng)計(jì)學(xué)意義。
1肺組織病理學(xué)觀察
本文針對(duì)花崗巖和大理巖進(jìn)行了4組三點(diǎn)彎曲巖石變形破裂過(guò)程微震和電荷感應(yīng)監(jiān)測(cè)試驗(yàn),其中75#和76#為完整花崗巖,77#和78#為預(yù)制裂紋花崗巖,79#和80#為完整大理巖,81#和82#為預(yù)制裂紋大理巖,所有試樣加載速度都為0.05kN/s,選取其中具有代表性的監(jiān)測(cè)數(shù)據(jù)作為研究對(duì)象,并對(duì)其中各參量數(shù)據(jù)進(jìn)行處理。表1為各試樣載荷峰值、峰值位移以及試樣達(dá)到載荷峰值時(shí)刻,圖3為各試樣破壞后的照片。
光學(xué)顯微鏡可見:NC組肺組織均可見完整的肺泡腔,肺泡結(jié)構(gòu)正常,肺間質(zhì)偶有散在的炎性細(xì)胞存在。MCMV組可見肺泡間質(zhì)水腫,肺泡壁增寬,內(nèi)可見大量炎性細(xì)胞浸潤(rùn),以單核細(xì)胞為主,上述病理符合MCMV間質(zhì)性肺炎的表現(xiàn)。SMV干預(yù)后間質(zhì)性炎癥浸潤(rùn)較MCMV組減輕,見圖1。
Figure 1. Observation of the lung tissues in each group under optical microscope (HE staining, ×200).
圖1各組肺組織的病理變化
2免疫組織化學(xué)檢測(cè)TLR-2蛋白表達(dá)的變化
肺組織中TLR-2的表達(dá)在NC組與MCMV組及不同SMV干預(yù)組之間差異均有統(tǒng)計(jì)學(xué)意義(P<0.05),SMV干預(yù)后TLR-2表達(dá)明顯少于MCMV組(P<0.05),且SMV1組與SMV2組和SMV3組相比,TLR-2表達(dá)更少,差異有統(tǒng)計(jì)學(xué)意義(P<0.05),而SMV2組和SMV3組兩組相比差異無(wú)統(tǒng)計(jì)學(xué)顯著性,見圖2。
Figure 2. The protein expression of TLR-2 in the lung tissues of each group determined by immunohistochemical staining(×200). Mean±SD.n=8.△P<0.05vsNC group;*P<0.05vsMCMV group;#P<0.05vsSMV1 group.
圖2各組肺組織TLR-2的免疫組織化學(xué)染色和半定量分析
3Westernblot檢測(cè)TLR-2蛋白表達(dá)的變化
感染MCMV后,MCMV組TLR-2表達(dá)增加,與NC組相比,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05);SMV1組、SMV2組和SMV3組的TLR-2表達(dá)較MCMV組下降,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05);且SMV1組下降較SMV2組和SMV3組更為明顯(P<0.05),而SMV2組和SMV3兩組之間相比差異無(wú)統(tǒng)計(jì)學(xué)顯著性,見圖3。
4ELISA檢測(cè)IFN-γ和MCP-1的含量
與NC組比較,MCMV組的IFN-γ和MCP-1含量明顯升高,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05);SMV干預(yù)后的IFN-γ和MCP-1含量明顯低于MCMV組(P<0.05),且SMV1組下降更明顯,與SMV2組和SMV3組相比,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05),而SMV2組和SMV3兩組之間的差異無(wú)統(tǒng)計(jì)學(xué)顯著性,見表1。
與MCMV組比較,SMV1組、SMV2組和SMV3組MCMV DNA含量顯著下降,差異有統(tǒng)計(jì)學(xué)顯著性(P<0.05),且SMV1組下降較SMV2和SMV3組更為明顯(P<0.05),而SMV2和SMV3組之間差異無(wú)統(tǒng)計(jì)學(xué)意義,見圖4。
Figure 3. The protein expression of TLR-2 in lung tissues was detected by Western blot. Mean±SD.n=8.△P<0.05vsNC group;*P<0.05vsMCMV group;#P<0.05vsSMV1 group.
圖3Westernblot檢測(cè)肺組織中TLR-2蛋白的表達(dá)
表1 各組小鼠肺組織IFN-γ和MCP-1的表達(dá)
△P<0.05vsNC group;*P<0.05vsMCMV group;#P<0.05vsSMV1 group.
Figure 4. The relative content of MCMV DNA in lung tissue of each group. Mean±SD.n=8.△P<0.05vsNC group;*P<0.05 MCMV group;#P<0.05vsSMV1 group.
圖4各組小鼠肺組織MCMVDNA的相對(duì)含量
感染MCMV后,病毒蛋白可以識(shí)別并啟動(dòng)TLRs介導(dǎo)的先天性抗病毒免疫反應(yīng)[5]。由于TLR-2位于細(xì)胞膜表面并識(shí)別病毒蛋白,與TLR-1或TLR-6共同作用激活MyD88依賴型及下游轉(zhuǎn)錄因子NF-κB信號(hào)通路誘導(dǎo)一系列促炎細(xì)胞因子、趨化因子及黏附分子的產(chǎn)生,調(diào)控病毒復(fù)制和/或宿主反應(yīng),最終影響病毒的發(fā)病機(jī)制[6]。在小鼠脾臟感染MCMV的研究中,TLR-2能促進(jìn)IFN-γ的產(chǎn)生[7]。IFN-γ還可以刺激多種先天性免疫細(xì)胞和免疫效應(yīng)器細(xì)胞活化,以激活適應(yīng)性免疫反應(yīng)發(fā)揮抗病毒作用[8]。有研究表明,感染MCMV的細(xì)胞可以通過(guò)間接效應(yīng)引起MCP-1的上調(diào),刺激轉(zhuǎn)錄因子NF-κB的激活[9],進(jìn)一步促進(jìn)IFN-γ的產(chǎn)生,以對(duì)抗MCMV感染,發(fā)揮保護(hù)效應(yīng)。而其它研究也表明,在感染期間,IFN-γ的產(chǎn)生也會(huì)促進(jìn)MCP-1的分泌[10]。而本實(shí)驗(yàn)研究結(jié)果與Niessner 等[2]研究結(jié)果一致。本實(shí)驗(yàn)結(jié)果顯示,感染MCMV后,小鼠肺組織發(fā)生病理?yè)p害,TLR2表達(dá)增加,IFN-γ和MCP-1明顯增多,影響MCMV的復(fù)制。因此,結(jié)合本研究結(jié)果,進(jìn)一步表明MCMV肺炎的發(fā)生是通過(guò)上調(diào)TLR2信號(hào)通路介導(dǎo)的炎癥反應(yīng),加重肺組織的病理?yè)p傷,最終影響MCMV的復(fù)制和合成。
辛伐他汀除了其有效降低膽固醇水平,減少心血管發(fā)病,同時(shí)具有多效性[1]。已有研究證明,辛伐他汀能抑制TLR-2的表達(dá)[2],并通過(guò)MyD88介導(dǎo)的途徑抑制下游NF-κB信號(hào)通路的激活[11-12],從而減少細(xì)胞因子的產(chǎn)生。在每一個(gè)炎癥反應(yīng)過(guò)程中,絕大多數(shù)細(xì)胞反應(yīng)需要NF-κB的轉(zhuǎn)錄活性[13]。這些效應(yīng)可能與辛伐他汀減少NF-κB的結(jié)合活性有關(guān)[14]。根據(jù)一系列證據(jù)表明,本實(shí)驗(yàn)結(jié)果顯示的MCMV肺炎通過(guò)辛伐他汀干預(yù)后,下調(diào)TLR-2介導(dǎo)的信號(hào)通路,從而使TLR-2表達(dá)下降;進(jìn)一步通過(guò)下調(diào)TLR-2-MyD88依賴性途徑致使IFN-γ和MCP-1分泌減少,從而使MCMV肺炎的病理?yè)p害得以減輕的這一過(guò)程似乎為辛伐他汀的“抗病毒”作用提供了一個(gè)較為合理的解釋。因此,目前的發(fā)現(xiàn)進(jìn)一步支持這一觀點(diǎn),通過(guò)干預(yù)TLRs信號(hào)通路可能成為減輕宿主細(xì)胞炎癥反應(yīng)的治療靶點(diǎn)。因此,辛伐他汀可以考慮作為一個(gè)特殊的抗炎藥物干預(yù)CMV感染,同時(shí)也可以通過(guò)干預(yù)CMV的復(fù)制周期發(fā)揮所謂的“抗病毒”作用。
本實(shí)驗(yàn)研究也發(fā)現(xiàn),在MCMV感染前給予辛伐他汀干預(yù)比在機(jī)體免疫力下降和感染后給藥效果更明顯。目前也有大量臨床研究表明,提前干預(yù)效果可能會(huì)更好。由于辛伐他汀的可利用性,特殊的抗炎作用及對(duì)CMV活性的影響,它可以考慮用于CMV感染前的預(yù)防用藥,以減少甚至阻斷CMV的感染和發(fā)病。
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(責(zé)任編輯: 盧 萍, 羅 森)
EffectofsimvastatinonexpressionofToll-likereceptor2inmousecytomegaloviruspneumonia
SUN Si1, CHEN Yu-ling2, ZUO Li-na2, ZHANG Wen-hui2, QIAO Yue-hua2
(1DepartmentofRespiratoryMedicine,TheCentralHospitalofXuzhou,Xuzhou221009,China;2DepartmentofRespiratoryMedicine,TheAffiliatedHospitalofXuzhouMedicalUniversity,Xuzhou221004,China.E-mail:pingcyl@126.com)
AIM: To investigate the effects of simvastatin on the expression of Toll-like receptor 2 (TLR-2), interferon-γ (IFN-γ) and monocyte chemoattractant protein-1 (MCP-1) in lung tissues of mice with mouse cytomegalovirus (MCMV) pneumonia and to explore the possible mechanism.METHODSMale BALB/c mice (6~8 weeks old,n=40) were randomly divided into 5 groups: normal control (NC) group, MCMV infection group, simvastatin group 1 (SMV1 group), simvastatin group 2 (SMV2 group), and simvastatin group 3 (SMV3 group). The mice in SMV1, SMV2 and SMV3 groups were gavaged with simvastatin (50 mg·kg-1·d-1for 7 d) 7 d before, on the same day of and 3 d after intraperitoneal injection of MCMV, while the mice in normal control group and MCMV infection group were gavaged with the same volume of normal saline. HE staining was used to observe the pathological changes of lung tissues in mice. Total tissue protein was extracted from the lung homogenates to detect the expression of TLR-2 by Western blot and immunohistochemical staining. Real-time PCR was used to analyse the content of MCMV DNA. The levels of IFN-γ and MCP-1 were measured by enzyme-linked immunosorbent assay (ELISA).RESULTSCompared with NC group, the pathological changes of the lung tissues of the mice in MCMV group showed alveolar interstitial edema, alveolar wall widening and a large number of inflammatory cells. The expression of TLR-2 in the lung tissues of the mice in model group was increased significantly. The content of MCMV DNA was increased, and the expression of IFN-γ and MCP-1 was also increased significantly. Compared with the mice in MCMV group, the pathological changes of the lung tissues of simvastatin groups showed that the inflammatory cells were decreased. The expression of TLR-2 was down-regulated. The content of MCMV DNA was decreased, and the levels of IFN-γ and MCP-1 were also decreased significantly. At the same time, the expression of TLR-2 and the content of MCMV DNA in SMV1 group were less than those in SMV2 and SMV3 groups (P<0.05), and no statistically significant difference between SMV2 and SMV3 groups was observed.CONCLUSIONSimvastatin down-regulates the TLR-2 signaling pathway, and reduces the expression of TLR-2 and replication of MCMV DNA, thus attenuating the pathological damage of the lung tissue. Early intervention with simvastatin plays an important role in preventing the infection of MCMV and reducing the inflammation.
Simvastatin; Cytomegalovirus; Toll-like receptor 2; Interferon-γ; Monocyte chemoattractant protein-1
R373.9; R363
A
10.3969/j.issn.1000- 4718.2017.10.025
1000- 4718(2017)10- 1886- 05
2016- 11- 16
2017- 05- 04
江蘇省六大人才高峰項(xiàng)目(No. 2014-WSN-043)
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