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摘要: 雌激素是一种多功能甾体类激素,不仅对女性生殖系统,且对内分泌、心血管、代谢系统等均具有明显作用。雌激素对多种肺部疾病具有潜在治疗价值,雌激素受体信号转导在呼吸道病毒感染过程中,参与机体固有免疫、适应性免疫、组织修复过程。动物实验证实,雌激素可以降低炎性因子水平,抑制炎症反应,降低病毒滴度等,从而提高呼吸道病毒感染小鼠的存活率。本文探讨雌激素对于呼吸道病毒感染的保护作用及其机制。Abstract: Estrogen is a multi-functional steroid hormone, which affects not only the female reproductive system, but also endocrine, cardiovascular, and metabolic systems. Estrogen has a potential therapeutic effect on a variety of lung diseases, and estrogen-receptor signaling plays a key role in the innate immunity, adaptive immunity and tissue repair in the course of infection of respiratory virus. Animal experiments have proved that estrogen therapy can reduce inflammatory factors, inhibit inflammatory response, reduce viral titer and so on, so as to improve the survival rate of mice infected with respiratory virus. In this paper, the protective effect of estrogen on the infection of respiratory virus and related mechanisms were reviewed.
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Keywords:
- respiratory infection /
- virus /
- estrogen /
- protective mechanism
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病毒性肺炎是指病毒感染呼吸道及肺部引起的炎症。近年来,由于流感病毒、严重急性呼吸综合征冠状病毒(severe acute respiratory syndrome coronavirus,SARS-CoV)、中东呼吸综合征冠状病毒(Middle East respiratory syndrome coronavirus,MERS-CoV)、新型冠状病毒(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)等的流行,病毒性肺炎已成为世界范围内公共卫生领域的重要疾病[1]。雌激素是一种具有广泛而重要生理作用的甾体类激素,可促进女性生殖器官发育并维持第二性征,同时对机体的其他系统如内分泌、心血管及呼吸系统均具有明显调节作用。相关研究证实,雌激素对多种肺部疾病,如哮喘、肺动脉高压、肺纤维化等也具有潜在的治疗价值[2]。
病毒性肺炎相关流行病学数据均呈现出男性患病率或病死率高于女性的特点[3-5],且相关动物实验及分子生物学研究提示,雌激素对呼吸道病毒感染具有保护作用。本文基于国内外现有研究,探讨其可能的保护机制。
1. 病毒性肺炎的病理机制
1.1 血管紧张素转换酶2效应
既往研究显示,SARS-CoV通过S蛋白与靶细胞表面的受体血管紧张素转换酶2(angiotensin converting enzyme 2,ACE2)结合,进而与宿主细胞膜融合,从而进入宿主细胞引起感染[6]。与SARS-CoV相同,SARS-CoV-2也以ACE2作为宿主细胞受体,从而促进病毒进入细胞[7-8]。最近一项研究发现,亚洲男性中表达ACE2的肺泡上皮细胞更为丰富,这可能解释了为何男性对SARS-CoV-2的易感性更高[9],然而此项研究样本量较小,结果外推需谨慎。
ACE2蛋白广泛分布于肺、十二指肠、空肠、回肠、心脏、脾脏、肾脏等器官[6, 10],而SARS-CoV-2除引起肺部症状外,还会导致腹泻、急性心肌损伤、肾衰竭等,推测这些症状可能与ACE2的分布密切相关。在病毒负荷量多、机体免疫力低下的情况下,病毒可能会导致全身多器官感染,甚至多器官功能衰竭[11]。
SARS-CoV-2的致病机理中,血管内皮的功能障碍占据主导地位,主要表现为病毒以ACE2为受体进入宿主细胞,导致人体凝血功能失调及抗炎功能丧失[12]。代谢综合征患者本身即存在内皮功能障碍,因此病毒与宿主细胞的ACE2结合后,病毒复制会激发免疫反应,进而产生大量的细胞因子,可能导致更严重的血管损伤,甚至是多器官功能衰竭或死亡[13]。ACE2在胰岛、血管内皮和脂肪组织中广泛表达,病毒与ACE2在这些组织中相互作用以及代谢综合征患者存在的促炎性环境,可能致使机体抗炎能力失调,从而表现出更严重的临床症状[14]。
1.2 病毒对免疫系统的影响
对SARS患者的血清检测发现,促炎细胞因子(白细胞介素-1、白细胞介素-6、白细胞介素-8等)水平明显升高,炎性因子的升高会进一步引起肺内单核巨噬细胞和中性粒细胞聚集,从而导致严重的肺损伤[15-16]。
动物实验亦证实,SARS病毒的快速复制可促进致病性炎症单核-巨噬细胞(inflammation monocyte macrophages,IMMS)流入,而IMMS是促炎细胞因子和趋化因子的主要来源,进而可引起广泛的血管渗漏、病毒特异性T细胞反应减弱,这些结果与SARS患者的血清检测及尸检结果相吻合[17]。
1.3 慢性疾病可能加重感染后果
伴有慢性疾病的新型冠状病毒肺炎(coronavirus disease 2019,COVID-19)患者,病情往往更严重,死亡风险更高。研究人员对1590例COVID-19患者的伴随疾病进行分层研究,结果显示伴有任何一种慢性疾病的患者比无慢性疾病患者的预后均更差。399例伴有一种慢性疾病的患者,需进入ICU治疗、使用呼吸机甚至死亡的概率均增加了70%,且伴有更多慢性疾病与更差的临床结果相关[18]。
其中与不良预后相关最常见的慢性疾病为高血压、2型糖尿病、慢性阻塞性肺疾病。由此可见,加重COVID-19的基础疾病与胰岛素抵抗(insulin resistance,IR)状态及心血管反应性密切相关。
2. 雌激素对病毒性肺炎的保护机制
2.1 雌激素受体信号调节的生理效应
雌激素受体信号参与调节体内多种生理效应,其不仅主导女性第二性征发育和维持、月经周期及女性体内环境的稳定,且在育龄女性中,参与调节先天性和适应性免疫系统中的细胞,如树突状细胞、巨噬细胞、CD8+T细胞的分化发育以及促进干扰素、促炎因子的产生,调节机体免疫应答[19]。
雌激素水平和雌激素受体信号转导对于维持成年男性生殖能力和身体健康状态也至关重要,通常雌激素缺乏会导致严重后果。据个案报道,存在两个雌激素受体-α等位基因突变的男性患者虽然体内雌激素水平很高,但其对雌激素基本无反应,因此呈现出严重的胰岛素抵抗、肥胖和早期心血管疾病迹象[20],这表明雌激素受体信号转导在维持葡萄糖代谢稳态及心血管反应中起重要作用。
2.2 雌激素可能通过调节血管紧张素转换酶2保护肺组织
动物实验采用敲除ACE2基因的SARS感染模型,证实ACE2是其感染的必需受体[21]。后续的实验却发现,ACE2基因敲除小鼠与野生型小鼠相比,对酸、PM2.5、博来霉素等表现出更严重的肺损伤[22-24],这表明在急性肺损伤发病机制中,ACE2对肺损伤的保护作用,即ACE2在冠状病毒感染过程中既充当了必需受体,又对宿主的肺损伤发挥了保护性作用。
动物实验亦表明,雌激素可下调肺、气道上皮细胞中ACE2 mRNA水平[25-26]。因此雌激素对宿主细胞ACE2水平进行调控,可能对限制病毒感染有益。
近期一项试验对COVID-19患者及对照组的ACE2表达水平进行了研究,结果显示COVID-19患者ACE2表达高于对照组,表明SARS-CoV-2病毒感染可能上调宿主细胞ACE2,进而促进其进一步侵袭;该研究还发现男性较女性患者高表达ACE2,表明男性可能对更易感[27]。
2.3 雌激素可减轻免疫炎症
一些季节性呼吸道疾病,例如流感病毒的动物实验证实,雌激素可减轻病毒诱导的肺部组织炎症及免疫病理改变,提高呼吸道病毒感染小鼠的存活率[28]。对SARS-CoV感染的雌性小鼠去卵巢后,会导致病毒滴度升高、血管渗漏增加、肺泡水肿和死亡率增加,以上变化均伴随着肺中IMMS的增加。这些数据表明雌激素受体信号转导抑制了IMMS在肺中的积聚和功能,从而降低雌性小鼠的死亡率[29]。
甲型流感病毒(influenza A virus,IAV)感染的动物实验显示,外源性雌激素治疗对IAV感染雌性小鼠的发病率和死亡率具有显著保护作用,作用机制包括产生γ-干扰素、肿瘤坏死因子-α以及促进对流感疫苗的高抗体反应[30-32]。在IAV感染过程中,雌二醇还可增加病毒特异性CD8+T细胞的百分比,进而提高小鼠的存活率,降低发病率[33]。
2.4 雌激素可直接抑制病毒复制
理论上,宿主一旦被感染,有两种防御策略来对抗病毒:一是减轻病毒所造成的组织损害,称为“疾病耐受性”;二是参与减少病毒复制反应,称为“宿主抵抗力”[34]。
呼吸道上皮通常是呼吸道病毒进入体内后首先遇到的组织,纤毛细胞是常见的靶点[35]。动物实验证实,用雌激素处理培养的雌性小鼠鼻上皮细胞,通过调节与细胞代谢相关的基因,可抑制病毒复制[36]。由于SARS-CoV-2主要在气道和肺泡上皮细胞中复制[37],女性雌激素受体信号转导可能通过对细胞代谢的影响,直接抑制病毒复制。
2.5 雌激素信号转导与慢性疾病的关系
女性绝经前,雌激素的合成缺陷常伴月经紊乱、无排卵性不孕等疾病,且与IR相关疾病具有很强的相关性,多囊卵巢综合征(polycystic ovary syndrome,PCOS)是最常见的表现[38]。女性绝经后,伴随雌激素的减少和IR的持续加重,也更易出现各种并发症[39]。动物实验也证实,雌性和雄性雌激素受体-α基因敲除的小鼠均表现出IR、葡萄糖耐量降低和肥胖症[40],这表明雌激素受体信号转导在维持体内葡萄糖稳态方面具有重要作用。
女性绝经后,心血管疾病发生率也随之增加,雌激素在其中发挥着重要作用:雌激素缺乏通过一氧化氮通路水平上调、抗氧化物产生减少、肾素-血管紧张素-醛固酮系统及内皮细胞水平失调等一系列途径,导致血管顺应性减低及心血管疾病发生率增加[41]。相关调查数据显示,COVID-19的发病率及患者死亡率与其伴随的慢性疾病密切相关,而这些慢性疾病往往与IR、血管反应性密切联系。因此对于正常月经周期的女性来说,雌激素受体信号转导对于呼吸道病毒感染可能具有保护作用。
3. 展望
雌激素作为一种多功能甾体类激素,其在SARS、MERS、IAV感染及COVID-19等疾病中所呈现出的性别差异值得我们深思:雌激素是否对呼吸道病毒的预防和治疗起到一定作用?
雌激素作为一种潜在的治疗措施,可能通过下调病毒感染的必需受体(ACE2)、减轻免疫炎症反应以及直接抑制病毒复制等,发挥其对于呼吸道病毒的特异性保护作用。从长远看,对绝经前雌激素缺乏女性、绝经后女性以及雌激素受体信号转导障碍的人群,进行恰当的雌激素补充治疗,可改善一系列与IR、血管反应性相关慢性疾病,从而降低对呼吸道疾病的易感性。但目前对相关假设的前瞻性临床研究仍较为有限,有待于进一步探索加以验证。
作者贡献:陈筱涵负责资料收集、论文撰写; 郁琦负责选题构思、论文修订。利益冲突: 无 -
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