劉俊輝,李春江,李玉濤,3*

(1.唐山愛爾眼科醫(yī)院眼科，河北 唐山 063000;2.冀東眼科醫(yī)院眼科，河北 唐山 063000;3.華北理工大學(xué)附屬醫(yī)院眼科，河北 唐山 063000)

白藜蘆醇對糖尿病大鼠視網(wǎng)膜病變的影響

劉俊輝1,2,李春江2,李玉濤2,3*

(1.唐山愛爾眼科醫(yī)院眼科，河北 唐山 063000;2.冀東眼科醫(yī)院眼科，河北 唐山 063000;3.華北理工大學(xué)附屬醫(yī)院眼科，河北 唐山 063000)

目的觀察白藜蘆醇(Resveratrol，RES)對糖尿病大鼠視網(wǎng)膜病變的影響并探討相關(guān)機(jī)制。方法清潔級健康雄性SD大鼠45只隨機(jī)分為對照組、模型組和RES組各15只。應(yīng)用鏈脲佐菌素腹腔注射制作糖尿病大鼠模型。造模后1周，RES組大鼠給予白藜蘆醇40 mg/kg(10 mL/kg)腹腔注射治療，1次/d，連續(xù)治療6周。治療結(jié)束后，測量各組大鼠血糖、體質(zhì)量，采用酶聯(lián)免疫吸附測定法檢測大鼠視網(wǎng)膜中腫瘤壞死因子α(tumor necrosis factor-α，TNF-α)和白細(xì)胞介素1β(interleukin-1β，IL-1β)含量，檢測大鼠血清中血管內(nèi)皮生長因子(vascular endothelial growth factor，VEGF)、缺氧誘導(dǎo)因子1α(hypoxia inducible factor-1α，HIF-1α)、 丙二醛(methane dicarboxylic aldehyde，MDA)和超氧化物歧化酶(superoxide dismutase，SOD)含量。結(jié)果模型組和RES組血糖高于對照組，體質(zhì)量低于對照組(P<0.05)；模型組與RES組血糖、體質(zhì)量差異均無統(tǒng)計(jì)學(xué)意義(P>0.05)。模型組和RES組大鼠TNF-α、IL-1β、VEGF、HIF-1α和MDA表達(dá)明顯高于對照組，RES組大鼠TNF-α、IL-1β、VEGF、HIF-1α和MDA表達(dá)低于模型組，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。模型組和RES組大鼠SOD表達(dá)明顯低于對照組，RES組大鼠SOD表達(dá)高于模型組，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。結(jié)論RES可抑制炎癥反應(yīng)和HIF-1α/VEGF通路，減輕氧化應(yīng)激損傷，從而改善糖尿病視網(wǎng)膜的血管病變。

糖尿病視網(wǎng)膜病變；白藜蘆醇；大鼠；鏈脲佐菌素

10.3969/j.issn.1007-3205.2017.11.016

糖尿病視網(wǎng)膜病變(diabetic retinopathy,DR)是糖尿病患者眼部最重要的并發(fā)癥，是糖尿病患者常見的微血管病變之一[1-2]。隨著人們生活水平的逐漸提高和生活方式的改變，DR發(fā)病率逐年增長[3]，同時(shí)伴隨眼部并發(fā)癥的病程逐漸縮短。病程20年以上的糖尿病患者大多伴有不同程度的DR。DR導(dǎo)致患者視力急劇下降，嚴(yán)重時(shí)會(huì)出現(xiàn)失明，給患者帶來極大痛苦[4]。目前，DR具體發(fā)病機(jī)制仍不十分清楚，而越來越多的研究表明早期DR特征表現(xiàn)為血管的神經(jīng)炎癥、血-視網(wǎng)膜屏障發(fā)生損害、出現(xiàn)氧化應(yīng)激損傷和細(xì)胞凋亡[5]。由此可見，早期對糖尿病患者進(jìn)行抗炎治療可能是預(yù)防DR的一種行之有效的干預(yù)措施。白藜蘆醇(Resveratrol，RES)具有抗炎、抗氧化應(yīng)激以及抗凋亡等特性，但是RES對DR抗炎方面的相關(guān)研究未見系統(tǒng)報(bào)道。本研究探討RES對糖尿病大鼠視網(wǎng)膜病變的抗炎作用及相關(guān)機(jī)制，旨在為臨床治療DR提供重要的理論依據(jù)。報(bào)告如下。

1 材 料 與 方 法

1.1 動(dòng)物模型及分組 清潔級健康雄性SD大鼠45只，體質(zhì)量200～250 g，由天津市實(shí)驗(yàn)動(dòng)物中心提供。所有SD大鼠隨機(jī)分為正常對照組15只、糖尿病模型組15只和RES組15只，所有大鼠進(jìn)行適應(yīng)性喂養(yǎng)7 d。模型組和RES組大鼠接受鏈脲佐菌素左下腹腹腔注射建立糖尿病模型(鏈脲佐菌素溶于生理鹽水中，按60 mg/kg進(jìn)行注射)，對照組注射等量的生理鹽水。鏈脲佐菌素注射72 h后尾靜脈測量血糖(血糖儀測定)，若血糖>16.7 mmol/L視為糖尿病模型制作成功。造模后1周，RES組大鼠給予40 mg/kg(10 mL/kg)白藜蘆醇單側(cè)腹腔注射治療，1次/d，連續(xù)治療6周。對照組和模型組大鼠每日給予等量生理鹽水腹腔注射。

1.2 試劑 白藜蘆醇、鏈脲佐菌素購自美國sigma公司。白細(xì)胞介素1β(interleukin-1β，IL-1β)及腫瘤壞死因子α(tumor necrosis factor-α，TNF-α)酶聯(lián)免疫吸附測定(enzyme linked immunosorbent assay，ELISA)試劑盒購自Abcam公司。其他試劑均購自北京博奧森生物技術(shù)有限公司。

1.3 實(shí)驗(yàn)方法 RES治療結(jié)束后每只大鼠稱體質(zhì)量，尾靜脈取血，血糖儀測量空腹血糖。大鼠腹腔注射10%水合氯醛(3 mL/kg)進(jìn)行腹腔麻醉，去雙側(cè)眼球，顯微鏡下分離視網(wǎng)膜，-80 ℃冰箱保存?zhèn)溆谩８鹘M大鼠摘除眼球后，暴露心臟，用真空采血管從腹主動(dòng)脈抽吸血液，離心后-80 ℃冰箱保存?zhèn)溆谩?/p>

1.4 TNF-α、IL-1β、血管內(nèi)皮生長因子(vascular endothelial growth factor，VEGF)、缺氧誘導(dǎo)因子1α(hypoxia inducible factor-1α，HIF-1α)、丙二醛(methane dicarboxylic aldehyde，MDA)和超氧化物歧化酶(superoxide dismutase，SOD)含量檢測 采用隨機(jī)數(shù)字表法將每組15只動(dòng)物分成3小組，每小組5只，5只進(jìn)行TNF-α和IL-1β檢測，5只行VEGF和HIF-1α檢測，另5只行MDA和SOD檢測。①視網(wǎng)膜加入組織裂解液，超聲粉碎后離心，取上清液蛋白定量，按ELISA試劑盒說明書檢測視網(wǎng)膜組織中TNF-α和IL-1β含量。②取大鼠血清，按ELISA試劑盒說明書檢測VEGF、HIF-1α、MDA和SOD含量。

1.5 統(tǒng)計(jì)學(xué)方法 應(yīng)用SPSS 17.0統(tǒng)計(jì)軟件分析數(shù)據(jù)。計(jì)量資料比較分別采用單因素方差分析和LSD-t檢驗(yàn)。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié) 果

2.1 各組大鼠血糖和體質(zhì)量比較 模型組和RES組血糖高于對照組，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)；模型組與RES組血糖差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。模型組和RES組體質(zhì)量低于對照組，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)；模型組與RES組體質(zhì)量差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。見表1。

組別血糖(mmol/L)體質(zhì)量(g)對照組6．74±0．76362．47±25．86模型組21．97±3．66?241．91±20．75?RES組22．68±2．69?248．29±18．43?F87．532168．605P0．0000．000

*P<0.05與對照組比較(LSD-t檢驗(yàn))

2.2 各組大鼠視網(wǎng)膜組織中IL-1β和TNF-α含量比較 模型組和RES組大鼠視網(wǎng)膜中IL-1β和TNF-α表達(dá)明顯高于對照組，RES組IL-1β和TNF-α表達(dá)低于模型組，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)，見表2。

組別IL?1βTNF?α對照組46．03±2．7425．48±2．03模型組72．65±2．28?61．32±4．67?RES組59．13±3．41?#42．85±5．26?#F104．533125．294P0．0000．000

*P<0.05與對照組比較 #P<0.05與模型組比較(LSD-t檢驗(yàn))

2.3 各組大鼠血清中VEGF和HIF-1α含量比較 模型組和RES組大鼠血清中VEGF和HIF-1α表達(dá)明顯高于對照組，RES組VEGF和HIF-1α表達(dá)明顯低于模型組，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)，見表3。

組別VEGF(ng/L)HIF?1α(μg/L)對照組98．25±12．620．32±0．03模型組167．61±13．88?0．64±0．09?RES組124．48±15．30?#0．45±0．07?#F95．37179．512P0．0000．000

*P<0.05與對照組比較 #P<0.05與模型組比較(LSD-t檢驗(yàn))

2.4 各組大鼠血清中MDA和SOD含量比較 模型組和RES組大鼠血清中MDA表達(dá)明顯高于對照組，RES組MDA表達(dá)低于模型組，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。模型組和RES組大鼠SOD表達(dá)明顯低于對照組，RES組SOD表達(dá)高于模型組，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。見表4。

組別MDASOD對照組6．72±1．53713．26±92．08模型組24．19±5．67?435．61±87．89?RES組14．28±3．07?#583．45±79．62?#F148．337120．106P0．0000．000

*P<0.05與對照組比較 #P<0.05與模型組比較(LSD-t檢驗(yàn))

3 討 論

DR是糖尿病最為常見的一種微血管并發(fā)癥，同時(shí)也是失明的一個(gè)主要原因[6]，其對患者自尊心有極大影響并給社會(huì)和家庭造成嚴(yán)重的負(fù)擔(dān)。目前DR的主要治療方法是疾病早期行激光光凝術(shù)以及疾病晚期應(yīng)用玻璃體切割手術(shù)，該方法對患者的視力造成損害并帶來不適感覺。因此，治療DR有效藥物的研究就顯得至關(guān)重要。

近年來，越來越多的研究證實(shí)DR是一種與炎癥密切相關(guān)的疾病，炎癥過程導(dǎo)致DR結(jié)構(gòu)和功能改變[7-8]。炎性細(xì)胞因子在DR的新生血管形成過程中起到了重要作用，在DR的發(fā)展過程中，視網(wǎng)膜炎癥和白細(xì)胞黏膜微血管(白細(xì)胞淤滯)促進(jìn)血-視網(wǎng)膜屏障的破壞[9]。炎性細(xì)胞因子的過度表達(dá)形成的炎性反應(yīng)可造成糖尿病個(gè)體視網(wǎng)膜出現(xiàn)損傷，其中炎性因子TNF-α和IL-1β[10-12]與DR的關(guān)系密切，參與了DR的發(fā)展進(jìn)程。TNF-α是由巨噬細(xì)胞或單核細(xì)胞活化后產(chǎn)生的一種多功能的炎癥因子，與血-視網(wǎng)膜屏障的破壞和血管細(xì)胞死亡呈正相關(guān)，被認(rèn)為是炎癥反應(yīng)的觸發(fā)器[13]，其增多可用來監(jiān)測DR的嚴(yán)重程度。IL-1β是IL-1家族的一員，在DR的進(jìn)程中發(fā)揮關(guān)鍵的作用。DR可導(dǎo)致IL-1β的增多，IL-1β及其他炎性因子可通過影響細(xì)胞黏附分子的表達(dá)、鈣超載、凋亡途徑等，進(jìn)一步加重糖尿病患者的視網(wǎng)膜病變[14-15]。慢性炎癥是DR發(fā)病機(jī)制中關(guān)鍵的一環(huán)，有研究報(bào)道減輕炎癥反應(yīng)可以減緩DR的進(jìn)展[16]。控制DR的炎癥反應(yīng)是治療DR的重要策略之一。

RES是廣泛存在于葡萄、虎杖等植物中的一種酚類植物抗毒素。大量研究表明其具有抗炎、心血管保護(hù)、抗凋亡、抗氧化、提高免疫活性、減肥降脂、抗癌、抗突變等特性[17-20]。RES可抑制前列腺癌中的IL-6信號(hào)通路，發(fā)揮抗腫瘤的作用[21]。Xu 等[22]證實(shí)RES可通過抑制細(xì)胞凋亡和炎癥反應(yīng)改善腎臟缺血和再灌注損傷。有研究應(yīng)用RES治療糖尿病大鼠的視網(wǎng)膜病變，發(fā)現(xiàn)其可抑制高血糖造成的谷氨酸攝取、谷氨酰胺合成酶的活性和表達(dá)的減少[23]。本研究觀察了RES對糖尿病大鼠視網(wǎng)膜內(nèi)TNF-α和IL-1β表達(dá)的影響，結(jié)果顯示模型組大鼠視網(wǎng)膜中TNF-α和IL-1β表達(dá)增多，RES有效抑制了DR大鼠視網(wǎng)膜中TNF-α和IL-1β的表達(dá)。因此，推斷抑制炎癥反應(yīng)可能是RES治療DR的分子生物學(xué)機(jī)制之一。

VEGF是調(diào)節(jié)視網(wǎng)膜血管滲漏和新血管形成主要的一種生長因子[24]。慢性高血糖刺激VEGF的合成和分泌[25]，炎性因子同時(shí)可誘導(dǎo)VEGF的分泌[26]，促進(jìn)視網(wǎng)膜新生血管的形成。VEGF由HIF-1α 轉(zhuǎn)錄調(diào)控，HIF-1α是影響新生血管形成的主要蛋白，其是調(diào)節(jié)高血糖狀態(tài)下VEGF表達(dá)的一種轉(zhuǎn)錄因子[24]。本研究結(jié)果顯示，模型組VEGF和HIF-1α的表達(dá)增多，而RES組兩者的含量下降。表明RES治療降低了VEGF和HIF-1α的表達(dá)。因此，推斷RES通過抑制HIF-1α/VEGF信號(hào)通路降低血管內(nèi)皮細(xì)胞的增殖，從而改善了糖尿病視網(wǎng)膜的血管病變。有研究發(fā)現(xiàn)，HIF-1α在DR中增多，抑制HIF-1α的表達(dá)可抑制DR中促炎因子IL-6和TNF-α的表達(dá)[27]。本研究顯示RES對糖尿病大鼠的血糖無明顯影響。故認(rèn)為RES治療后血清中VEGF和HIF-1α的減少是抑制炎癥因子過度表達(dá)的重要機(jī)制。

氧化應(yīng)激同樣也是影響DR過程中的重要因素，大量的動(dòng)物和臨床研究證實(shí)了DR出現(xiàn)了氧化應(yīng)激損傷[28]。MDA和SOD在許多研究中均被用作氧化應(yīng)激的相關(guān)指標(biāo)。MDA是氧化應(yīng)激狀態(tài)下脂質(zhì)過氧化反應(yīng)的產(chǎn)物，與氧化應(yīng)激和脂質(zhì)過氧化程度呈正相關(guān)[29]，通常作為氧化應(yīng)激損傷的常用標(biāo)志物，MDA的升高被認(rèn)為是氧化損傷中脂質(zhì)過氧化的結(jié)果。氧化應(yīng)激損傷同時(shí)會(huì)造成抗氧化的防御系統(tǒng)出現(xiàn)損害，影響抗氧化物酶[30]。DR中MDA表達(dá)增多、SOD活性下降[31]。RES具有抗氧化應(yīng)激特性，可通過SIRT1/FOXO3a通路減輕高血糖導(dǎo)致的腎小管氧化應(yīng)激損傷，同時(shí)可影響甲氨喋呤引起的大鼠回腸組織的氧化應(yīng)激。本研究結(jié)果顯示，糖尿病導(dǎo)致了氧化應(yīng)激指標(biāo)MDA表達(dá)增多和SOD活性下降，提示DR大鼠處于氧化應(yīng)激狀態(tài)，而RES治療減輕了高血糖造成的氧化應(yīng)激損傷。說明抗氧化應(yīng)激作用是RES治療DR的又一重要機(jī)制。

綜上所述，RES可降低糖尿病大鼠視網(wǎng)膜中TNF-α、IL-1β的表達(dá)，通過抗炎作用起到對視網(wǎng)膜的保護(hù)作用。同時(shí)，RES抑制了HIF-1α/VEGF信號(hào)通路，可能通過此機(jī)制影響視網(wǎng)膜新生血管的形成，從而改善糖尿病視網(wǎng)膜的血管病變。RES治療同樣減輕了高血糖造成的氧化應(yīng)激損傷。在今后的工作中將會(huì)繼續(xù)深層次探討RES的藥理作用，尤其是在眼科疾病中的基礎(chǔ)和臨床研究，從而為DR乃至其他眼部疾病患者的治療提供理論依據(jù)。

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TheeffectsofResveratrolondiabeticratswithretinopathy

LIU Jun-hui1,2, LI Chun-jiang2, LI Yu-tao2,3*

(1.DepartmentofOphthalmology,TangshanAierEyehospital,HebeiProvince，Tangshan063000,China; 2.DepartmentofOphthalmology,JidongOphthalmologyHospital,HebeiProvince，Tangshan063000,China; 3.DepartmentofOphthalmology,NorthChinaUniversityofScienceandTechnologyAffiliatedHospital，HebeiProvince,Tangshan063000,China)

ObjectiveTo observe the effects of Resveratrol(RES) on diabetic rats with retinopathy, and to explore its mechanism.MethodsForty-five cleaning degree healthy male SD rats were randomly divided into 3 groups, control group,model group and RES group(n=15/group). The diabetic rats model were established by streptozotocin intraperitoneal injection. One week after modeling, rats in RES group was administrated intraperitoneally with RES(40 mg/kg, 10 mL/kg) once daily for consecutive 6 weeks. After treatment, the blood glucose and body weight of different groups were measured. The expression of tumor necrosis factor alpha(TNF-α) and interleukin-1β(IL-1β) in retina of different groups were detected by enzyme linked immunosorbent assay(ELISA). The expression of vascular endothelial growth factor(VEGF), hypoxia inducible factor-1α(HIF-1α), methane dicarboxylic aldehyde(MDA) and superoxide dismutase(SOD) in serum of different groups were detected by ELISA.ResultsThe blood glucose of model group and RES group was higher than control group, body weight of model group and RES group was lower than control group(P<0.05), there were no significantly difference between model group and RES group(P>0.05). The expressions of TNF-α, IL-1β, VEGF, HIF-1α and MDA in model group and RES group were higher than that of control group. The e expressions of TNF-α, IL-1β, VEGF, HIF-1α and MDA in RES group were lower than that of model group(P<0.05). The expression of SOD in model group and RES group was lower than that of control group. The expression of SOD in RES group was higher than that of model group(P<0.05).ConclusionRES could inhibit inflammatory reaction, suppresses HIF-1α/VEGF pathway and reduces oxidative stress injury, then ameliorates vascular lesions in diabetic retina.

diabetic retinopathy； Resveratrol； rats； streptozotocin

·論著·

2017-05-22；

2017-06-23

劉俊輝(1978-)，女，河北唐山人，唐山愛爾眼科醫(yī)院主治醫(yī)師，醫(yī)學(xué)學(xué)士，從事眼科疾病診治研究。

*通訊作者。E-mail：Liyutao@jidongeye.com

R587.26

A

1007-3205(2017)11-1310-05

(本文編輯：許卓文)