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   大连医科大学学报  2022, Vol. 44 Issue (1): 69-74      DOI: 10.11724/jdmu.2022.01.14
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血红素氧合酶-1在胃肠道疾病中的作用研究进展
任萍萍1,2, 段志军1    
1. 大连医科大学附属第一医院 消化内科,辽宁 大连 116011;
2. 大连医科大学附属第二医院 消化内科,辽宁 大连 116027
摘要:血红素氧合酶-1(hemeoxygenase-1, HO-1)是血红素代谢过程中的限速酶,催化血红素裂解生成等分子的一氧化碳(carbon monoxide, CO)、胆绿素和Fe2+。HO-1是一种公认的保护剂,具有抗炎、抗氧化的作用,并参与调控细胞增殖、凋亡、自噬等重要生命过程,对各种不同组织的创伤均具有保护作用。多项研究显示,HO-1在非甾体抗炎药(non-steroidal anti-inflammatory drugs, NSAIDs)相关性消化道损伤、炎症性肠病(inflammatory bowel disease, IBD)、肠缺血再灌注损伤、消化道肿瘤、胃瘫等多种消化道疾病中均有适应性表达,并起到保护胃肠组织和细胞的重要作用。本文就HO-1在消化道疾病防治中的作用及机制研究进行综述。
关键词血红素氧合酶-1    炎症性肠病    消化道肿瘤    缺血/再灌注损伤    
Role of HO-1 in gastrointestinal diseases
REN Pingping1,2, DUAN Zhijun1    
1. Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China;
2. Department of Gastroenterology, the Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China
Abstract: Hemeoxygenase-1 (HO-1) is a rate-limiting enzyme in heme metabolism, which cleaves heme into equimolar quantities of carbon monoxide (CO), biliverdin and Fe2+.HO-1 is a recognized protective agent, which has anti-inflammatory and antioxidant effects and participates in the regulation of cell proliferation, apoptosis, autophagy and other important life processes, and plays a protective role in various tissue injuries. Multiple studies have shown that HO-1 plays an important role in protecting gastrointestinal tissues and cells and has adaptive expression in a variety of gastrointestinal diseases including non-steroidal anti-inflammatory drugs (NSAIDs) related gastrointestinal injury, inflammatory bowel disease disease(IBD), intestinal ischemia-reperfusion injury, gastrointestinal tumor, gastroparesis. We reviewed the role and mechanism of HO-1 in the prevention and treatment of gastrointestinal diseases.
Keywords: hemeoxygenase-1    inflammatory bowel diseases    gastrointestinal tumor    ischemia/reperfusion injury    

血红素氧合酶(hemeoxygenase,HO)是血红素代谢过程中的限速酶。血红素在HO的催化作用下被氧化裂解产生等分子的一氧化碳(carbon monoxide,CO)、胆绿素和Fe2+。HO-1、HO-2、HO-3是HO家族中的三个异构体成员。尽管他们催化相同的生化反应,却是不同基因的产物,在组织和细胞中的表达模式存在差异。HO-3缺乏酶活性,目前仅有其在大鼠体内表达的相关报道[1]。HO-2(36.5 kDa)主要在脑和睾丸中组成性表达,参与调节生殖细胞和神经细胞产物;有研究报道,HO-2也在内皮、肾脏和肝脏细胞中呈低水平表达[2]。HO-1(32 kDa),即热休克蛋白32(heat shock protein-32,Hsp32),是诱导型HO异构体,正常情况下在组织中的表达量低,而当机体处于应激状态时,HO-1表达明显增加并参与保护性机制。多种有害介质刺激和病理状态可诱导HO-1表达上调,包括重金属、放射物质、氧自由基(reactive oxygen species,ROS)、氮自由基(reactive nitrogen species,RNS)、炎症细胞因子、病原体相关分子模式(pathogen associated molecular patterns,PAMP)、缺氧、缺血、休克等。HO-1具有抗炎、抗氧化的作用,参与调节细胞的增殖、凋亡和自噬等重要生理过程[3],在脏器组织中发挥积极的保护作用。转录因子核因子E2相关因子(nuclear factor erythroid-2, Nrf2)[4]和诱导抑制因子Bach1[5]是HO-1转录过程中的主要调控因子。这两个调控因子参与钴原卟啉(cobalt-protoporphyrin-Ⅸ,CoPP)对HO-1的诱导过程[6]。Nrf2在应对氧化应激中发挥关键作用,参与诱导多种抗氧化基因的表达,包括HO-1[7]。相反,Bach1是生理条件下HO-1的抑制因子,值得注意的是,Bach1是通过与Nrf2上对HO-1基因起调节作用的Maf识别原件(Maf-recognition elements,MARE)结合来抑制HO-1的表达[8]。应激状态下,Bach1离开细胞核,Nrf2与DNA结合诱导HO-1的表达[9]。Bach1缺失的情况下HO-1呈持续性表达[5],减轻氧化应激诱导的损伤[10-11]

HO-1的诱导被普遍认为在炎症及各种病理状态下发挥细胞保护作用,因此众多学者为探究其在各种疾病中的潜在治疗价值开展了广泛的研究。本文针对HO-1在胃肠道疾病中作用的最新研究进展进行总结。

1 HO-1在非甾体抗炎药相关性胃肠病中的作用

非甾体抗炎药(non-steroidal anti-inflammatory drugs, NSAIDs)是环氧化合酶(cyclooxygenase,COX)抑制剂,具有减少促炎症物质合成的作用,用于疼痛、发热及炎症的治疗,是全球处方量最大的药物之一,具有重要的临床价值。然而,NSAIDs能够引起多种不良反应,其中最常见的是胃肠道和心血管并发症,对其在临床的应用产生限制。NSAIDs可导致消化道黏膜完整性缺失、黏膜出血,削弱消化道黏膜固有抗氧化防御体系,抑制细胞再生,抑制细胞向损伤处上皮层迁移[12]。多项研究显示,NSAIDs刺激损伤消化道黏膜的过程中,HO-1被诱导表达,并发挥保护作用。Song等[13]的研究发现,吲哚美辛可对猫食管上皮细胞产生细胞毒性作用,显著降低细胞活性,以药物诱导食管上皮细胞HO-1表达可提高细胞活性,而抑制HO-1的表达则加重细胞损伤。吲哚美辛促进胃黏膜促炎因子表达增加,包括胞内黏附分子-1(intercellular adhesion molecule 1, ICAM-1)、血管细胞黏附分子-1(vascular cell adhesion molecule 1, VCAM-1)、白介素1β(interleukin 1β, IL-1β)和单核细胞趋化蛋白(monocyte chemotactic protein 1, MCP-1),白介素6(interleukin 6, IL-6)和肿瘤坏死因子α(tumor necrosis factor α, TNF-α)等,引起中性粒细胞浸润增加[14-15],诱导胃黏膜细胞凋亡[16],造成胃黏膜损伤、溃疡形成。诱导HO-1表达可逆转吲哚美辛刺激导致的上述炎症物质生成及炎症细胞浸润,抑制细胞凋亡,起到保护胃黏膜的作用。Yoda等[17]的研究发现,吲哚美辛导致SD大鼠小肠黏膜出血性损伤,诱导性氮氧合酶(inducible nitric oxide synthase,iNOS)表达增加及髓过氧化物酶(myeloperoxidase,MPO)活性增强,给予HO-1促进剂上调HO-1的表达,上述过程被逆转,小肠黏膜损伤减轻[17]。另外,许多药物发挥抗NSAIDs相关消化道损伤作用的机制涉及HO-1。Yoda等[17]通过大鼠体内实验发现,兰索拉唑通过诱导HO-1的表达减轻吲哚美辛刺激引起的小肠黏膜损伤。Song等[13, 18]发现异泽兰黄素通过ERK(extracellular signal-regulated kinase)途径诱导HO-1的表达,对吲哚美辛引起的食管上皮细胞和回肠平滑肌细胞损伤具有保护作用。

2 HO-1在糖尿病性胃轻瘫中的作用

糖尿病性胃轻瘫是糖尿病胃肠植物神经病变的常见症状,由于胃排空延迟引起厌食、恶心、早饱、呕吐、腹胀的临床症状,严重影响患者生活质量。Cajal间质细胞(interstitial cell of Cajal, ICC)在正常胃排空过程中起重要作用。在糖尿病胃轻瘫发病过程中,氧化应激导致ICC损伤,而上调HO-1对ICC具有保护作用,能够改善糖尿病小鼠胃排空[19]。另一动物实验发现,电针刺激ST-36通过上调M2巨噬细胞中HO-1的表达对ICC起到保护作用[20]

3 HO-1在肠缺血/再灌注损伤中的作用

多种临床疾病引起肠道血流阻断后再通的过程中可伴有肠缺血/再灌注(ischemia/reperfusion, I/R)损伤,包括肠系膜动脉闭塞、小肠移植、腹主动脉瘤手术、体外循环、绞窄疝、创伤和休克等,与较高的发病率和死亡率相关。研究表明,HO-1在I/R介导的小肠损伤中起到抗炎的细胞保护作用[21]。事先给予CoPP促进HO-1的表达能够减轻小肠I/R损伤[22]。谷氨酰胺、二硫代氨基甲酸吡咯烷等可通过促进HO-1的表达抑制炎症细胞因子生成、增加微血管的灌注,从而改善肠I/R损伤的预后[23-24]。HO-1基因敲除小鼠其肠道I/R损伤更严重,然而HO-1过表达的小鼠其肠道I/R损伤减轻[25-26]。另外,HO-1代谢产物也可减轻肠I/R损伤。HO-1催化含铁血红素分解成CO、胆绿素和Fe2+。低浓度的CO和胆绿素均可以减轻肠I/R动物模型的肠组织损伤[27-29]。临床研究中发现,HO-1在缺血性结肠炎患者结肠组织中呈高表达可能是机体应对肠缺血性损伤的一种保护机制[30]

4 HO-1在炎症性肠病中的作用

炎症性肠病(inflammatory bowel disease, IBD)指病因未明的非特异炎症性肠道疾病,主要包括溃疡性结肠炎(ulcerative colitis, UC)和克罗恩病(Crhon's diseases, CD)。UC病变累及结肠和直肠,而CD可引起消化道任何部位的受累,以回盲部受累最为常见。近年,越来越多的研究者致力于HO-1对IBD治疗作用的研究。三硝基苯磺酸(trinitrobenzene sulfonic acid, TNBS)诱导结肠炎模型组小鼠结肠组织中HO-1的表达反应性增加,发挥保护作用[31]。以CoPP或血红素诱导促进HO-1的表达,可减轻TNBS或葡聚糖硫酸钠(dextran sulfate sodium, DSS)刺激所造成实验动物的肠道炎症损伤;而以锡原卟啉(tin-protoporphyrin, SnPP)、锌原卟啉(Zinc-protoporphyrin, ZnPP)抑制HO-1的表达,可加重肠道损伤[31-34]。如上文所述,Nrf2和Bach1是HO-1上游重要的转录因子,分别可促进和抑制HO-1的表达。采用基因工程技术对小鼠Nrf2基因进行敲除,可上调HO-1的转录和表达,从而分别减轻IBD模型组动物的肠道炎症,而Bach基因敲除组小鼠的实验结果恰好相反[35-36]。HO-1催化血红素分解产生CO,研究表明,CO或CO释放分子(CO releasing molecule, CORM)可抑制有害细胞因子产生,从而减轻IBD模型动物肠道损伤的程度[37-41]。另外,多种药物在缓解肠道炎症过程中发挥的作用是由于其促进了HO-1的表达而实现的,包括5氨基水杨酸(5-aminosalicylate, 5-ASA)、富氢水、曲尼斯特、白术-蒲公英提取物、6-姜烯酚、槲皮苷、类黄酮[42-51]

5 HO-1在消化道肿瘤中的作用

HO-1在消化道肿瘤疾病中所起的作用存在争议。Ren等[52]的研究发现,食管鳞癌(esophageal squamous cell carcinoma,ESCC)患者肿瘤组织中HO-1的表达增加,且HO-1表达的水平与肿瘤分级有关,表达水平越高,食管癌分级越高。通过抑制HO-1的表达可抑制ESCC细胞系(TE-12细胞和Eca109细胞)增殖,提高ROS水平,促进肿瘤细胞凋亡。相反,Andrés等[53]通过研究阐述,人类结直肠癌(colorectal cancer,CRC)组织中HO-1表达增加,并具有抗肿瘤作用,HO-1的高表达与患者的生存期延长相关;他们的团队采用1, 2-二甲基肼(1,2-dimethylhydrazine,DMH)诱导构建CRC动物模型并通过研究发现,随着肿瘤的进展,HO-1的表达逐渐增加,可诱导肿瘤细胞周期停滞、细胞凋亡从而实现抗肿瘤作用。另一体外试验显示,人结肠癌细胞系(HCT116细胞)的HO-1表达高于人肠上皮细胞系(NCM356细胞),CORM-3可促进HO-1催化产物CO的产生,并抑制HCT116细胞的增殖[54]。小肠腺癌组织中HO-1高表达的患者发生胰腺转移浸润的几率低,生存期更长[55]。然而,HO-1的表达对肿瘤细胞的影响可能存在复杂的多面性,而不仅仅是单向的促进或抑制关系。Yin等[56]发现,胃癌患者肿瘤组织中的HO-1表达增加,HO-1的高表达水平越高,其分化程度越良好,淋巴结转移阴性率越高。而该团队却在后续的体外研究中发现,胃癌细胞系(MKN-45细胞)中HO-1表达上调,促进了基质金属钛酶(matrix metallopeptidase 9,MMP9)和血管内皮生长因子(vascular endothelial growth factor A,VEGF-A)的表达,进而诱导MKN-45细胞对顺铂耐药;而抑制HO-1的表达可使MKN-45细胞对顺铂的敏感性增加。有研究指出,CRC患者肿瘤组织中HO-1的表达增加,细胞内HO-1总体表达水平越高肿瘤分化越好,然而胞核内HO-1表达水平越高,肿瘤分化程度却越低。HO-1抑制剂ZnPP能够增强化疗药物THP对CRC细胞的毒性作用[57]。综上,HO-1对消化道肿瘤可能具有双刃剑的作用,且受到多种背景因素的影响,其具体机制尚待进一步深入研究阐明。

HO-1及其代谢产物已成为生命科学领域中的研究热点之一,在消化道疾病中具有重要的生物学意义,有可能为治疗NSAIDs相关性损伤、IBD、肠缺血再灌注损伤、消化道肿瘤、胃瘫等多种消化道疾病提供新的思路。但目前对HO-1及其代谢产物作用的探究仍局限于动物和细胞实验水平,有待进一步通过开展丰富的临床研究进行验证。

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文章信息

任萍萍, 段志军
REN Pingping, DUAN Zhijun
血红素氧合酶-1在胃肠道疾病中的作用研究进展
Role of HO-1 in gastrointestinal diseases
大连医科大学学报, 2022, 44(1): 69-74.
Journal of Dalian Medical University, 2022, 44(1): 69-74.
通信作者
段志军,教授。E-mail:cathydoctor@sina.com.

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