修回日期: 2024-09-26
接受日期: 2024-10-21
在线出版日期: 2024-10-28
肾上腺皮质激素释放激素家族成员及其受体广泛分布于中枢及外周组织, 参与机体心血管、代谢、免疫反应和炎症等方面的调节. 促肾上腺皮质激素释放激素受体2(corticotropin-releasing hormone receptor 2, CRHR2)为其特异性受体之一, 它可以缓冲应激导致的肠道高敏感性、影响肠道微生物组成和多样性、具有很强的抗炎能力, 同时还可以调节肠上皮细胞的增殖和凋亡过程, 促进肠粘膜修复. 近年来研究表明, 在炎症性肠病(inflammatory bowel disease, IBD)患者的结肠组织中检测到CRHR2的含量与正常人体肠道组织存在明显差异, 有人认为 CRHR2可能是潜在的IBD治疗靶点. 本文对CRHR2的生理功能及其与IBD之间的临床相关性进行综述, 旨在探索CRHR2在IBD治疗中的具体作用机制和潜在的临床应用价值, 为将来开发更多有效的IBD的治疗手段提供依据.
核心提要: 促肾上腺皮质激素释放激素受体2(corticotropin-releasing hormone receptor 2, CRHR2)作为促肾上腺皮质激素的特异性受体之一, 在中枢和肠道均有广泛分布, 参与机体多系统和内环境稳态的调节. 本文就从CRHR2的生理功能及其与炎症性肠病的内在联系进行综述.
引文著录: 刘浏, 金怡丹, 范一宏. CRHR2在炎症性肠病中的研究进展. 世界华人消化杂志 2024; 32(10): 742-749
Revised: September 26, 2024
Accepted: October 21, 2024
Published online: October 28, 2024
Members of the corticotropin-releasing hormone family and their receptors are widely distributed in central and peripheral tissues and are involved in the regulation of the cardiovascular system, metabolism, immune function, and inflammatory response in the body. Corticotropin-releasing hormone receptor 2 (CRHR2), one of specific receptors for corticotropin releasing factor, attenuates stress-induced intestinal hypersensitivity, influences intestinal microbial composition and diversity, has strong anti-inflammatory capacity, and regulates the proliferation, migration, and apoptosis of intestinal epithelial cells, and promotes intestinal mucosal repair. In recent years, studies have shown that the levels of CRHR2 in the colon tissue of patients with inflammatory bowel disease (IBD) are significantly different from those in normal human intestinal tissue, and it has been suggested that CRHR2 may be a potential therapeutic target for IBD. This paper reviews the physiological functions of CRHR2 and its clinical relevance to IBD, with the aim of exploring its specific mechanism of action and potential clinical application in the treatment of IBD, so as to provide a basis for the development of more effective therapeutic means for IBD in the future.
- Citation: Liu L, Jin YD, Fan YH. Progress in research of corticotropin-releasing hormone receptor 2 in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2024; 32(10): 742-749
- URL: https://www.wjgnet.com/1009-3079/full/v32/i10/742.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v32.i10.742
炎症性肠病(inflammatory bowel disease, IBD)是一种病因不明的慢性非特异性肠道炎性疾病, 好发于中青年, 呈慢性反复性发作, 以黏液血便、腹泻、腹痛、消瘦和贫血为主要表现, 病程长, 并发症严重, 复发率高, 可致中毒性巨结肠、肠穿孔、肠梗阻、肠出血、癌变, 严重影响患者生活质量. IBD主要包括2种疾病类型, 即溃疡性结肠炎和克罗恩病[1]. 近十几年来我国IBD的发病率和患病率均显著上升[2]. 关于IBD的病因和发病机制目前尚不完全明确, 但越来越多的证据表明遗传、环境、肠道菌群失调及免疫调节紊乱等多种因素共同引起IBD的发生发展. 社会心理应激是IBD发病和持续发展过程中的诱导因素之一. 当机体遭遇应激时, 下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal, HPA)轴启动, 导致下丘脑分泌促肾上腺皮质激素释放激素(corticotropin-releasing hormone, CRH), 经由靶向作用于其特异性受体, 即CRH受体, 调节机体在应激状态下HPA轴功能, 触发一系列复杂的生物效应, 参与调节机体行为、心血管、代谢、免疫功能和内环境的稳定[3,4]. CRH受体包括促肾上腺皮质激素释放激素受体1(corticotropin-releasing hormone receptor 1, CRHR1)和促肾上腺皮质激素释放激素受体2(corticotropin-releasing hormone receptor 2, CRHR2), CRHR1在参与压力应激诱导的焦虑和恐惧、胃肠道功能和炎症反应及HPA轴的激活等方面的调节作用已相对明确[5-9], 然而, CRHR2的生理功能及与IBD之间的联系尚未完全阐明, 本文就CRHR2在IBD中的研究进展做一综述.
CRH受体为经典的Ⅱ型G蛋白偶联受体, 有4个胞外结构域、4个胞内结构域和7个跨膜结构域, 其C端位于胞膜内, 膜内的第3个环区可能是G蛋白偶联区, N端位于胞膜外, N端糖基化对CRH受体与CRH及其相关肽的结合有重要作用[10]. CRH受体有两种类型, CRHR1和CRHR2. CRHR2在人类中主要有三个有功能的亚型, CRHR2α、CRHR2β、CRHR2γ, 三者C端最后377个氨基酸序列相同, 主要区别在于N端, α、β、γ亚型N端分别有34、61和20个氨基酸, 对CRHR2与配体间的相互作用有重要影响[11]. CRHR2α主要在大脑中表达, 尤其是在下丘脑和嗅球中. CRHR2β则分布于心肌、骨骼肌、胃肠道及脑血管和脉络丛的上皮细胞. 与啮齿类动物相比, 人类CRHR2β仅在心脏和骨骼肌中微弱表达. CRHR2γ主要局限于大脑[12]. 在CRH家族中, 尿皮质素(UCN1、UCN2和UCN3)是与CRH具有序列同源性的多肽. CRH家族成员通过与CRH受体相互作用来发挥其功能[13]. UCN1可与CRHR1和CRHR2相结合, 但UCN2和UCN3是CRHR2的专属配体, 因为它们都对CRHR2具有选择性亲和力[14].
CRH家族是内分泌、自主神经、行为和内脏反应对压力和应激的关键介质[6,15-17], CRHR2作为受体之一, 参与机体多种生理功能的调节.
CRH被认为在维持人类怀孕和开始分娩中起关键作用[18]. 众所周知, 前列腺素参与分娩的所有过程, 包括胎膜剥离、宫颈成熟和子宫肌收缩[19]. 研究发现[20], UCN1、UCN2和UCN3可以通过CRHR2精细调节前列腺素的分泌, 从而促进怀孕期间子宫的功能状态. Amin等[21]研究发现CRHR2基因变异会促进卵巢中相关基因的染色质负激活, 从而可能影响女性的生理周期和排卵. Kawka-Paciorkowska等[22]研究发现CRHR2在妊娠第41周前自发开始分娩的对照组中具有统计学较高的表达率, 在过期妊娠中, CRHR2受体上调受到干扰, 而CRHR1的表达没有变化. 这些证据表明CRHR2在人体妊娠和分娩过程中起着重要作用.
CRHR2被认为介导了UCN或CRH本身的致厌食作用[23,24]. Rühmann等[25]研究显示, 给予CRHR2选择性拮抗剂能够显著减弱CRH诱导的厌食症. Nozu等[26]研究表明CRHR2选择性拮抗剂可以完全阻止腹部手术诱导的胃排空抑制, 并且CRHR1选择性拮抗剂无此作用. Oka等研究[27]使用全外显子组测序技术发现CRHR2基因变异与患者进食障碍有关. Alcántara-Alonso等[28]研究表明CRHR2参与调节食欲相关基因前阿黑皮素原和神经肽Y的表达. Chen等[29]研究发现脑室内注射CRHR2在热应激导致的享乐性摄食行为减少中发挥重要作用. 通过以上这些证明, CRHR2参与了机体摄食行为的调控.
CRH及其受体在介导心理压力引起的生理反应方面起着广泛作用, 与压力相关的情绪行为存在密切联系[30,31]. 目前较多证据表明CRHR1在介导CRH引发的焦虑和抑郁行为方面起着关键作用[32-34]. CRHR1基因缺陷或CRHR1拮抗剂的使用可以明显减轻实验小鼠焦虑或抑郁样行为[35,36]. 然而, 有研究显示[37]CRHR2基因缺陷的斑马鱼在实验中表现出明显增强的焦虑样行为. Valdez等[38]研究显示, UCN3(特异性结合CRHR2)注射后的大鼠表现出压力相关的焦虑样行为减少. 以上证据表明, CRHR2在情绪行为调节方面起着积极作用.
CRHR2在心肌细胞和全身脉管系统中均有表达, CRHR2表现出积极的心脏变时和正性肌力作用使它被认为是治疗心力衰竭的潜在治疗靶点[39]. Mori等[40]研究表明CRHR2拮抗剂能够减少3', 5'-环磷酸腺苷的产生, 对压力超负荷诱导的心功能障碍具有保护作用. Bale等[41]研究结果显示, CRHR2可以通过调节平滑肌细胞的血管内皮生长因子水平而控制平滑肌细胞增殖和毛细管的形成. 这些结果表明CRHR2在调节心血管系统稳态方面具有一定作用.
学习和记忆的调节是CRH的作用之一[42,43]. 乙酰胆碱是脑内与学习记忆功能密切相关的一种化学物质[44]. 有研究显示[45]CRH和UCN1通过CRHR1刺激海马乙酰胆碱的释放, 而UCN2和UCN3通过CRHR2抑制海马乙酰胆碱的释放来调节认知功能, 包括注意力、学习和记忆. Hafenbreidel等[46]研究也发现, CRHR2的激活会破坏与记忆功能密切相关的肌动蛋白-肌球蛋白细胞骨架的稳定性, 从而影响正常的记忆功能.
CRH是下丘脑分泌的, 可以刺激糖皮质激素释放, 在机体调节炎症过程中起重要作用. 多项动物实验和临床研究表明[47-52], CRH参与机体多种炎症反应, 如炎症性关节炎、实验性自身免疫性葡萄膜视网膜炎、实验性自身免疫性脑脊髓炎、艰难梭菌毒素诱导的肠道炎症、类风湿性关节炎、溃疡性结肠炎、桥本甲状腺炎等. CRHR1被证实具有促炎作用[53]. CRHR2则被证实与抗炎作用有关. Im等[54]研究显示, CRHR2基因缺陷的小鼠肠道炎症较野生型小鼠明显加重, 且在CRHR2拮抗剂处理的小鼠中也得到同样的结果. Kubat等[55]研究中显示, 急性胰腺炎模型中CRHR2基因缺陷的小鼠表现出更重的腺泡细胞炎症和坏死. Moffatt等[56]研究也发现, CRHR2在气道炎症中也有抑制作用. Tsatsanis等[57]研究表明, CRHR2可以通过抑制巨噬细胞中肿瘤坏死因子-α(tumor necrosis factor alpha, TNF-α)的释放来调节炎症反应. 以上证据表明, CRHR2参与调节机体多系统的炎症反应过程.
Smagin等[58]研究发现, 下调CRHR2可选择性地减轻 CRH和UCN诱导的HPA轴激活. Coste等[59]研究显示CRHR2基因敲除小鼠表现出促肾上腺皮质激素释放的早期终止, 且在应激后90分钟皮质酮水平仍然升高, 表明CRHR2参与HPA轴的驱动和维持阶段, 对HPA轴应激反应起到调节功能. Deng等[37]研究同样表明, CRHR2基因缺陷会导致机体HPA轴失调. HPA轴是神经内分泌系统的重要部分, 通过激素的释放和反馈机制, 参与机体多种生理功能的调节, 如昼夜节律、心血管、消化、免疫系统、认知、应激反应、性行为以及能量贮存和消耗等[60]. 由于CRHR2能够影响HAP轴的功能故其还可能对机体的昼夜节律、新陈代谢、能量存储与消耗等机能方面存在调节作用, 这还有待进一步研究确定.
胃肠道是受压力应激影响的外周器官之一, CRH信号途径在其中发挥着重要作用[61,62]. 越来越多的证据显示[52,63,64]CRH与IBD之间存在密不可分的联系, 并可能参与该病的发病机制. 临床观察[65,66]显示, IBD患者肠黏膜中CRHR1上调, CRHR2下调. CRHR2可能通过以下途径改善IBD的肠道炎症, 促进肠黏膜修复.
过度的压力和应激会对许多外周器官的功能产生短期和持久的影响, 包括消化道[67-69]. 应激能够改变肠道运动功能、刺激或增强肠道炎症, 被认为是IBD的关键诱发因素之一[70,71]. CRH和受体家族的成员是应激反应的关键调节因子, 被认为与慢性炎症(包括IBD)的调节有关[4]. 实验证据支持外周或中枢注射CRH可明显增强肠道运动, 并促进肠道炎症的发展[67,72]. 在胃运动功能方面, 研究显示[73-75], CRHR2主要参与压力诱导的胃排空延迟, 同时这个效应能被CRHR2选择性拮抗剂阻断. 另外, 有研究发现[76-78]CRHR1与应激导致的焦虑抑郁行为、结肠功能亢进、水样腹泻及内脏痛觉过敏有关, 同时CRHR1选择性拮抗剂可消除或减少这些效应. Nozu等[79]研究发现, 神经降压素受体1激动剂能够缓解CRH诱导的内脏超敏反应, 提高内脏疼痛阈值, 但是这种效应能够被CRHR2拮抗剂所逆转. Million等[80]研究发现, CRHR2选择性激动剂UCN2能够缓解刺激导致的内脏疼痛, 但这这种效应能够被CRHR2拮抗剂所抑制. 结合上述证据, 在机体应对应激导致的内脏感觉和运动反应时, CRHR2可能起着与CRHR1相反的生理作用, 能够改善应激导致的肠道高敏感性, 减轻内脏疼痛, 调节胃肠道蠕动功能, 缓解IBD的消化道症状.
IBD患者中的白细胞介素-6(interleukin- 6, IL-6)、白细胞介素-1β(interleukin- 1β, IL-1β)、TNF-α等炎症因子明显升高, 且这些炎症因子与疾病的严重程度存在明显相关性. CRH具有重要的促炎作用[81]. Agelaki等[53]同样发现CRH能增强脂多糖诱导的炎症因子如TNF-α、IL-1β、IL-6的产生, 而CRHR1拮抗剂预处理能减轻炎症反应, 表明CRHR1拮抗剂可抑制炎症因子产生, 而CRHR1有促炎作用. 相较于CRHR1的促炎作用, 有研究发现[54], CRHR2基因敲除小鼠在葡聚糖硫酸钠(dextran sulphate sodium, DSS)诱导的IBD模型中炎症反应较野生型小鼠明显加重. Rodriguez等[82]研究中也发现, CRHR2 mRNA的表达量与炎症因子IL-6水平呈负相关. Hoffman等[83]通过给DSS诱导的IBD模型小鼠注射CRHR2拮抗剂后, 发现炎症因子IL-6、TNF-α增加, 肠道疾病活动度加重. Gong等[84]研究也验证了这一结论, 并且该实验还显示给予CRHR2选择性激动剂UCN2注射后能降低DSS诱导的IBD模型小鼠结肠组织IL-6、TNF-α和炎症趋化因子的水平, 减轻肠道炎症反应. 这些结果均提示 CRHR2能降低IBD炎症因子水平, 具有与CRHR1促炎效应相反的抗炎作用.
肠道微生物是健康免疫系统的组成部分, 在营养、免疫、新陈代谢和对病原体的防御等方面起着重要作用[85]. 肠道菌群中的一些有害菌可以通过免疫细胞的相互作用或其代谢产物诱导炎症细胞因子产生, 导致肠道损伤[86]. IBD患者与健康个体之间的肠道菌群组成和多样性方面存在显著不同[87,88]. 肠道菌群的组成和多样性的改变是IBD发生发展的重要因素[89]. Wang等[90]关于外周CRH给药是否对IBD模型小鼠肠道菌群存在影响的研究中发现IBD模型小鼠肠道微生物多样性低于正常对照组, 给予CRH后进一步加重了这种下降趋势, 并且肠道有害细菌数量明显增加. CRHR1和CRHR2作为CRH的两种受体, 可能在调节肠道菌群方面起着不同作用. 有研究显示[91], CRHR1会通过破坏原有肠道菌群的稳态而介导肠道损伤. 还有研究[92]提示丁酸钠能够改善肠道菌群失衡, 增加厚壁菌门细菌数量, 导致这种效应的机制极有可能是通过增加CRHR2的表达实现的. 这些证据表明, CRHR2能够影响肠道菌群的组成和多样性, 这对改善IBD肠道炎症起着非常重要的作用.
肠上皮通过细胞间相互作用形成屏障, 涉及紧密连接和基于钙粘蛋白的粘附连接等动态结构, 构成了抵御外部环境的最大和最重要的屏障[93]. 肠道上皮屏障的破坏会对肠壁产生负面影响, 使病原体侵入固有层, 从而干扰局部免疫并引起肠道炎症[94]. IBD患者存在着不同程度的肠道上皮屏障功能损坏. 压力应激会导致肠上皮屏障功能的破坏, 导致IBD等胃肠疾病的恶化[95,96]. CRH作为压力应激的关键介质之一, 可明显增加肠道通透性, 促进肠道炎症的发展. 有研究显示[97], 肠上皮细胞中CRHR2表达上调有助于恢复被破坏的紧密连接和脂多糖导致的上皮屏障功能障碍. Wang等[90]研究中发现3%DSS诱导的IBD模型小鼠的肠上皮细胞中可以见到明显的潘氏细胞化生, 外周CRH给药后进一步增加了潘氏细胞化生. Li等[91]研究发现, CRHR1会导致肠道通透性增加, 破坏肠道屏障功能, 而CRHR2能够激活肠道干细胞, 促进肠上皮修复, 改善肠道屏障功能. Sun等[98]研究发现, 肥大细胞稳定剂JM25-1能够促进肠道屏障损伤修复, 其作用机制是通过通过下调CRHR1、上调CRHR2的表达来实现的. Gong等[84]研究也发现给予IBD模型小鼠注射UCN2(特异性结合CRHR2)后可以改善小鼠肠道上皮细胞增殖, 减少细胞凋亡, 而给予CRHR2特异性拮抗剂注射后会加重小鼠肠上皮细胞的凋亡. 以上结果均提示CRHR2可能在维持完整的肠道上皮屏障功能方面起到重要作用.
IBD患者发生焦虑和抑郁的风险高于普通人群[99,100]. 焦虑和抑郁能够影响IBD患者疾病的病程, 甚至加重疾病活动性[101,102]. 慢性压力是焦虑和抑郁的危险因素[103]. CRH及其受体作为应对压力的主要介质, 与压力相关的焦虑、抑郁情绪行为存在密切联系[104]. 研究显示[105]CRHR1拮抗剂能够有效阻断焦虑或抑郁样行为, 且较多证据表明CRHR1在促进焦虑和抑郁行为方面起着重要作用[32-34]. 然而, Kishimoto等[106]研究中观察到相较于CRHR1基因缺陷的小鼠, CRHR2基因缺陷小鼠在实验中表现出明显增强的焦虑样行为. Todorovic等[107]的研究中也观察到CRHR2基因缺陷小鼠在强迫游泳试验和悬尾试验中的抑郁样行为明显增强. 这些证据表明, CRHR2参与抗焦虑和抑郁行为, 起着与CRHR1相反的情绪行为调节功能.
CRH是神经内分泌系统应对应激压力反应的关键神经介质, CRH和CRH相关肽及其受体形成了一个重要的生理系统, 影响了广泛的行为、心血管、代谢、炎症和免疫功能. 目前CRH和CRHR1拮抗剂在动物实验和临床试验中已广泛开展. CRH拮抗剂CRF 9-41被证明可以改善应激诱导的大鼠肠道通透性的增加[108]. 在动物实验中, CRHR1拮抗剂NBI 35965改善结肠转运功能, 消除应激引起的内脏痛觉过敏[109]. 一项包括重度抑郁症患者在内的II期开放性临床试验表明, 在不损害基线或外源性CRH干预后促肾上腺皮质激素和皮质醇分泌活性的情况下, CRHR1拮抗剂R121919可有效降低抑郁和焦虑评分[110]. 虽然CRHR2拮抗剂或激动剂在临床实验中研究相对CRHR1较少, 但在IBD及相关疾病中, 我们发现CRHR2的激活可以调控焦虑和抑郁情绪, 缓解内脏敏感性, 调节胃肠道运动, 改善肠道菌群组成和多样性, 同时还可以降低炎症因子, 影响上皮细胞的增殖和凋亡过程, 促进肠黏膜修复, 其在IBD中的研究和应用前景是充满希望的, 未来的研究将进一步探索CRHR2在IBD治疗中的具体作用机制和潜在的临床应用价值. 同时, 随着对IBD发病机制的深入理解, 更多创新的治疗手段将不断涌现, 为IBD患者带来更有效的治疗方法.
学科分类: 胃肠病学和肝病学
手稿来源地: 浙江省
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科学编辑:张砚梁 制作编辑:张砚梁
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