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Article(id=1208791313470845773, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208791311621157694, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.11.14, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1611590400000, receivedDateStr=2021-01-26, revisedDate=1618416000000, revisedDateStr=2021-04-15, acceptedDate=null, acceptedDateStr=null, onlineDate=1766127907387, onlineDateStr=2025-12-19, pubDate=1638028800000, pubDateStr=2021-11-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766127907387, onlineIssueDateStr=2025-12-19, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766127907387, creator=13701087609, updateTime=1766127907387, updator=13701087609, issue=Issue{id=1208791311621157694, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='11', pageStart='1061', pageEnd='1164', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766127906946, creator=13701087609, updateTime=1766128932678, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208795613920104935, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208791311621157694, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208795613920104936, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208791311621157694, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1148, endPage=1152, ext={EN=ArticleExt(id=1208791313751864155, articleId=1208791313470845773, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress on the protective effect and mechanism of dietary supplements on heat stroke, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

With the persistent increase of global temperature, the incidence of heatstroke is rising yearly. The impairment of the intestinal barrier function induced by heat stroke leads to endotoxemia. Systemic inflammatory response syndrome and multiple organ dysfunction syndrome ensue, which are the main causes of heat stroke death. And heat stroke is characterized by rapid deterioration and extremely high fatality. However, unlike other critical diseases, heat stroke is preventable and controllable.According to domestic and foreign researches, dietary supplements can enhance the intestinal barrier and alleviate the inflammatory response in heat stroke. This article reviews the research progress of dietary supplements in the protection of heat stroke and its mechanism in recent years, hoping to provide the reference for the prevention and treatment of heat stroke.

, correspAuthors=Mei-Tang Wang, authorNote=null, correspAuthorsNote=
*E-mail:
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随着全球气温的不断升高，热射病的发病率逐年增高。在热应激的作用下，肠道屏障功能受损，导致内毒素入血，其继发的系统性炎症反应综合征及多器官功能障碍综合征是热射病死亡的主要原因。热射病一旦发病，进展迅速且致死率高，但与其他危重病不同的是，热射病是可预防的。国内外文献报道，膳食补充剂在热射病中有着保护肠道屏障、减轻机体炎症反应的作用。该文综述了近年来膳食补充剂对热射病的防护作用及其机制研究进展，以期为热射病的预防及治疗提供参考与借鉴。

, correspAuthors=王美堂, authorNote=null, correspAuthorsNote=
王美堂，E-mail：
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王少康，硕士研究生，主要从事热射病的相关研究

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王少康，硕士研究生，主要从事热射病的相关研究

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王少康，硕士研究生，主要从事热射病的相关研究

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膳食补充剂对热射病的防护作用及机制研究进展
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王少康 1 , 张笑婷 2 , 李磊 1 , 陈基快 3 , 夏新宇 1 , 许硕贵 1 , 王美堂 1, *
解放军医学杂志 | 综述 2021,46(11): 1148-1152
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解放军医学杂志 | 综述 2021, 46(11): 1148-1152
膳食补充剂对热射病的防护作用及机制研究进展
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王少康1, 张笑婷2, 李磊1, 陈基快3, 夏新宇1, 许硕贵1, 王美堂1, *
作者信息
  • 1海军军医大学附属长海医院急诊科，上海 200433
  • 2海军军医大学附属长海医院麻醉学部，上海 200433
  • 3海军军医大学海军医学系卫生毒理学教研室，上海 200433

    • 王少康，硕士研究生，主要从事热射病的相关研究

通讯作者:

王美堂，E-mail：
Research progress on the protective effect and mechanism of dietary supplements on heat stroke
Shao-Kang Wang1, Xiao-Ting Zhang2, Lei Li1, Ji-Kuai Chen3, Xin-Yu Xia1, Shuo-Gui Xu1, Mei-Tang Wang1, *
Affiliations
  • 1Department of Emergency, Changhai Hospital Affiliated to Naval Medical University, Shanghai 200433, China
  • 2Faculty of Anesthesiology, Changhai Hospital Affiliated to Naval Medical University, Shanghai 200433, China
  • 3Department of Health Toxicology, Faculty of Naval Medicine of Naval Medical University, Shanghai 200433, China
出版时间: 2021-11-28 doi: 10.11855/j.issn.0577-7402.2021.11.14
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摘要
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随着全球气温的不断升高，热射病的发病率逐年增高。在热应激的作用下，肠道屏障功能受损，导致内毒素入血，其继发的系统性炎症反应综合征及多器官功能障碍综合征是热射病死亡的主要原因。热射病一旦发病，进展迅速且致死率高，但与其他危重病不同的是，热射病是可预防的。国内外文献报道，膳食补充剂在热射病中有着保护肠道屏障、减轻机体炎症反应的作用。该文综述了近年来膳食补充剂对热射病的防护作用及其机制研究进展，以期为热射病的预防及治疗提供参考与借鉴。

热射病  /  膳食补充剂  /  肠道屏障  /  系统性炎症反应综合征

With the persistent increase of global temperature, the incidence of heatstroke is rising yearly. The impairment of the intestinal barrier function induced by heat stroke leads to endotoxemia. Systemic inflammatory response syndrome and multiple organ dysfunction syndrome ensue, which are the main causes of heat stroke death. And heat stroke is characterized by rapid deterioration and extremely high fatality. However, unlike other critical diseases, heat stroke is preventable and controllable.According to domestic and foreign researches, dietary supplements can enhance the intestinal barrier and alleviate the inflammatory response in heat stroke. This article reviews the research progress of dietary supplements in the protection of heat stroke and its mechanism in recent years, hoping to provide the reference for the prevention and treatment of heat stroke.

heat stroke  /  dietary supplements  /  intestinal barrier  /  systemic inflammatory response syndrome
王少康, 张笑婷, 李磊, 陈基快, 夏新宇, 许硕贵, 王美堂. 膳食补充剂对热射病的防护作用及机制研究进展. 解放军医学杂志, 2021 , 46 (11) : 1148 -1152 . DOI: 10.11855/j.issn.0577-7402.2021.11.14
Shao-Kang Wang, Xiao-Ting Zhang, Lei Li, Ji-Kuai Chen, Xin-Yu Xia, Shuo-Gui Xu, Mei-Tang Wang. Research progress on the protective effect and mechanism of dietary supplements on heat stroke[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (11) : 1148 -1152 . DOI: 10.11855/j.issn.0577-7402.2021.11.14
正文
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随着全球气温的不断升高，热射病(heat stroke，HS)的发病率亦逐年增高。HS进展十分迅速，即使是经过充分的院内治疗，也难以避免严重后遗症的发生，因此探寻各种预防措施以降低HS的发病率及病残率是当前研究的重点。HS致肠道屏障破坏，促使内毒素入血，进展为系统性炎症反应综合征(systemic inflammatory response syndrome，SIRS)及多器官功能障碍综合征(multiple organ dysfunction syndrome，MODS)，是其致死的重要原因。因此，改善肠道屏障功能并提高其对高温的耐受能力，缓解SIRS及MODS的进展可有效防护HS的发生发展。近年来有研究发现膳食补充剂(dietary supplements，DS)能提高机体对热应激的抵抗能力，并减轻HS对机体的损害[1-4]。本文综述HS的发生机制以及DS对HS的防护作用，以期为后续研究及临床救治提供参考。
1 热射病及其发生机制
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HS是由于暴露于热环境和(或)剧烈运动导致机体产热与散热失衡，以核心体温>40 ℃及中枢神经系统异常为特征，如精神状态改变、抽搐或昏迷等，并伴有多器官损害的危及生命的临床综合征[5-6]。根据发病原因及易感人群的不同，HS可分为经典型HS(classic heat stroke，CHS)与劳力型HS(exertional heat stroke，EHS)。CHS多见于老年人、孕妇、儿童及有慢性基础疾病的人群，主要由于被动暴露于热环境而致病[7-10]。EHS多见于运动员、军人、建筑工人等，主要由于高强度体力活动而致病。据国外的调查资料，在夏季热浪期间，CHS人群发病率为(17.6~26.5)/10万，其中老年人病死率>50%[8,11-12]；由于EHS常见于健康的年轻人，且通常能及时发现并治疗，因此病死率较低(<5%)[12]。
HS的主要发病机制可概括为从体温调节机体散热尚能平衡产热的代偿阶段发展到失代偿阶段，最终心输出量不足以应对高体温调节需求。由于核心体温持续升高，导致直接细胞毒性效应及炎症反应，形成恶性循环，最终导致多器官衰竭[13]。
肠道是重要的消化及免疫器官，亦含有大量细菌，这些细菌可产生大量内毒素[14]。在生理状态下，肠黏膜屏障起着防止细菌与毒素入血的作用[15]，而在HS病程中，由于缺血缺氧、氧化应激及胰蛋白酶的作用，肠道屏障功能受损[16-17]，肠道免疫功能障碍同样在HS的进展中起重要作用[18]，以上损伤因素的相互作用导致细胞间紧密连接受损、肠道通透性增加，细菌与内毒素通过肠道毛细血管或淋巴管入血，最终导致内毒素血症[19-20]。还有研究表明，预防肠黏膜屏障损伤可能是中暑患者及中暑动物模型的有效治疗方式[20-22]。
热应激的直接损伤会导致炎症反应，使肠道通透性增加，肝脏在热应激下缺血坏死，解毒能力下降，最终导致细菌及内毒素入血[16-18,23-24]，在两者的共同作用下炎性细胞激活，释放白细胞介素(IL)-1β、IL-6、肿瘤坏死因子(TNF)-α等炎性介质[14]，参与机体防御反应以抵御外来伤害。炎性细胞及其释放的细胞因子在导致内皮细胞损伤、促进血小板黏附、释放氧自由基及脂质代谢产物的同时，会进一步激活炎性细胞，并在体内形成“瀑布效应”，导致炎性介质含量剧增，扩大炎症反应，最终导致SIRS及MODS。
2 膳食补充剂的防护作用及其机制
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美国食品药品管理局将DS定义为一种增加每日总摄入量的饮食成分，包括蛋白质、氨基酸、维生素、矿物质及草本植物等。Rautiainen等[25]研究发现，正确合理地使用DS可以减少肿瘤、心血管疾病、糖尿病等疾病的发病并改善预后。军人作为HS的高发人群，高强度训练下的营养丢失、多种恶劣条件对生理的影响以及对力量与耐力等训练的高要求，使他们更需要DS以减轻恶劣条件对人体的不利影响，提高部队的作战能力。目前DS已广泛应用于军队中以预防疾病及提高部队的战斗力。Knapik等[26]对美军使用DS情况的调查结果显示，陆军、海军、空军及海军陆战队中男性使用DS的比例分别为55%、60%、60%及61%，精英军事团体(海军特种作战部队、陆军突击队及陆军特种部队)中男性使用DS的比例为76%。
DS在日常生活及临床中的应用均十分广泛。Bailey等[27]的调查显示，美国1岁及以上人口中，有49%的人群使用DS，且各类DS的使用比例均呈现随年龄增长而增高的趋势，其中多种维生素与矿物质使用最多(33%)，其次是植物类(14%)及氨基酸(4%)。以上均反映了DS应用的广泛性。
2.1 蛋白质与氨基酸
蛋白质是生命活动最主要的载体，承担着多种生物学功能，是生物体内最重要的生物大分子之一。氨基酸是蛋白质构成及消化吸收的基本单位，较多学者关注并研究了氨基酸作为DS对HS的防护作用。谷氨酰胺是胃肠道细胞(特别是肠道淋巴细胞)的供能物质，也是体内抗氧化物质谷胱甘肽的前体[28]。有研究发现，谷氨酰胺能增强热应激小鼠热休克蛋白70的表达，并提高小鼠的存活率[29-30]。Soares等[1]发现在小鼠饮食中补充谷氨酰胺可减轻热暴露带来的体温升高及肠道通透性增加。Evans等[31]研究发现，谷氨酰胺能预防细胞因子介导的人结肠上皮细胞凋亡。丙氨酰谷氨酰胺常作为肠外营养的组成部分，在体内可以分解为谷氨酰胺与丙氨酸。高强度运动造成的体液丢失，以及运动中肠道缺血导致的水与电解质吸收减少在EHS的发生发展中起重要作用。Hoffman等[32]发现丙氨酰谷氨酰胺可增强水及电解质的吸收，从而明显提高机体代谢水平，抵抗肌肉蛋白的分解，增强肌肉运动能力，延缓疲劳的产生，提示可以通过补充DS提高机体的活动耐量及对水与电解质的吸收能力，从而预防HS的发生。Chen等[33]发现，在肉鸡饮食中加入苏氨酸可以减轻脂多糖造成的肠道屏障功能破坏及全身炎症反应。精氨酸是一氧化氮产生的底物，一氧化氮可以提高巨噬细胞的杀菌作用。其次，作为一种有效的免疫功能调节剂，精氨酸还能调节淋巴细胞的增殖及成熟，以及淋巴细胞和巨噬细胞的分化。精氨酸缺乏可能导致免疫功能不全，并增加危重患者的感染风险[34]。Yi等[35]对猪进行实验研究发现，精氨酸可以减轻热应激对猪肠道屏障的损伤作用。Huang等[36]研究发现，精氨酸可减轻热应激对小鼠肠道屏障的损伤作用。
2.2 维生素与矿物质
微量元素通过参与构成酶活性中心、激素及维生素等在体内发挥十分重要的生理功能。谷胱甘肽过氧化物酶是一种广泛存在于机体内的过氧化物分解酶，可催化谷胱甘肽(glutathione，GSH)生成氧化型谷胱甘肽，并将有毒的H2O2还原成H2O。硒是谷胱甘肽过氧化物酶的组成成分，Liu等[2]研究发现，在猪的膳食中增加硒及维生素E的含量，可减轻热应激对肠屏障完整性的影响，该作用与减轻氧化应激有关。Chang等[37]在热应激后的小鼠腹腔内注射维生素C，结果发现其可以减轻HS小鼠的炎症反应及下丘脑损伤。以上研究提示，对于需肠外营养的HS重症患者，可以添加一些对HS有明确防护作用的DS，以增强患者对HS的抵抗能力。目前关于维生素与矿物质对HS防护作用的研究很少，可能与维生素与矿物质在体内含量较少有关。
2.3 中药类
随着对中医药研究的深入，中医药在HS的防治中也发挥了越来越重要的作用。Wan等[3]将85例中暑患者随机分为常规组与大黄组，前者接受常规治疗，后者在常规治疗基础上补充大黄，结果发现，与常规组比较，大黄组炎性因子的表达受到抑制、肝肾功能改善、疾病严重程度评分降低，不利事件发生率下降。Cheng等[38]在热应激前连续3 d给予大鼠白藜芦醇灌胃，发现白藜芦醇可通过抗氧化及抗炎作用改善热应激状态下大鼠肠道的结构及功能。Sandner等[39]对Caco-2细胞、线虫及肉鸡进行研究，发现人参提取物中的人参皂苷可以降低热应激状态下Caco-2细胞中热休克蛋白1A(HSPA1A)的表达，并上调紧密连接蛋白(CLDN)3、CLDN1及密封蛋白(OCLN)的表达；可以提高线虫在热应激下的存活时间；还可改善热应激下肉鸡的生长状态。姜黄素是从姜科、天南星科植物的根茎中提取的一种二酮类化合物，Szymanski等[40]招募了8名志愿者，通过在高温环境下长跑来模拟EHS，并每日口服500 mg姜黄素，通过检测肠道脂肪酸结合蛋白(intestinal fatty acid-binding protein，I-FABP)评估肠道屏障功能，检测炎性因子评估机体炎症水平，检测生理紧张指数(physiological strain index，PSI)评估患EHS的风险，连续干预3 d后，结果显示姜黄素可以改善热应激下的肠道屏障受损，减轻炎症反应并降低PSI评分。Wang等[41]在脂多糖处理的Caco-2细胞中加入汉黄芩素，结果发现汉黄芩素可以通过抑制Toll样受体4(Toll like receptor 4，TLR4)、髓样分化因子88(myeloid differentiation factor 88，MyD88)、转化生长因子β激活激酶1(TGF-β activated kinase 1，TAK1)介导的核因子(NF)-κB途径减少促炎因子的释放并维持肠道的屏障功能。
2.4 益生菌
益生菌作为特殊的DS，当摄取足够数量时，对宿主健康有益，具有调节肠道功能紊乱、改善肠道菌群结构、减轻肠道疾病产生的炎症、提高肠道屏障功能等作用[42]。目前，益生菌多用于常见的消化系统疾病如新生儿坏死性结肠炎、感染性腹泻、炎症性肠病等[43]。在热应激研究领域，益生菌在畜牧业中的应用已取得一定成果并推广应用。研究发现，多种益生菌的使用可显著提高鸡、鸭、猪、牛等禽畜对热应激的耐受能力，在高温季节能够降低其死亡率，提高其摄食量、产蛋率等生产性能指标[44-45]。Sorokulova等[46]使用枯草芽孢杆菌BSB3株于热应激前2 d灌服大鼠，然后对其进行热应激(45 ℃高温环境暴露25 min)干预，通过观察大鼠的相关损伤指标及肠道病理变化，发现预先服用益生菌可明显降低大鼠的热应激反应。本课题组前期研究发现，对大鼠连续7 d灌服地衣芽孢杆菌(Bacillus licheniforms，BL)活菌可显著改善热应激(环境温度42 ℃，相对湿度65%，暴露1 h)大鼠的肝肾功能，并减少血清中IL-1β、IL-6、TNF-α等炎性因子的表达，BL对热应激的防护机制是调节肠道菌群，缓解热应激早期出现的肠道损伤，维持肠道屏障功能，从而缓解热应激大鼠的病情。对大鼠的肠道菌群进行深入研究发现，罗姆布茨菌(Romboutsia)属在热应激大鼠粪便中的丰度升高，使用BL可降低该菌在肠道内的比例，但罗姆布茨菌属与热应激的关系仍须进一步验证[47]。
2.5 其他
二十碳五烯酸(eicosapentaenoic acid，EPA)是一种多不饱和脂肪酸，具有清理血管中胆固醇及三酰甘油的功能。Xiao等[4]发现，EPA可明显减轻热应激对Caco-2细胞间紧密连接的破坏，保护肠道屏障功能。乳制品含有丰富的营养，Prosser等[48]发现，通过在小鼠饮食中添加牛初乳及羊奶的方法，可以减轻热应激后小鼠肠道通透性的增加。Marchbank等[49]对12名运动员进行研究发现，牛初乳可以减轻热应激下肠道通透性的增加，增强运动能力，并预防中暑。Davison等[50]发现肌肽锌与牛初乳联合使用可以减轻热应激后肠道屏障功能的损伤。
3 总结与展望
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随着全球热浪的频发、人口老龄化的加剧以及官兵作训的需要，更多关于HS发生发展的研究逐渐开展。在HS发病过程中，肠道屏障功能破坏是关键环节，而肠道屏障破坏继发的内毒素血症、SIRS及MODS已成为HS致死的主要原因。DS是对日常饮食的补充，且具有减轻热应激下肠道屏障损伤及炎症反应的作用，可作为防治HS的重要方法。谷氨酰胺具有明确的HS防护效应，可在生活训练等方面应用。乳制品中的乳铁蛋白有提高肠道屏障功能、抗氧化及减轻机体炎症反应的作用，但其对HS的治疗作用目前研究较少，因此加强学科间的交叉研究、促进科研成果向临床应用的转化十分重要。益生菌作为一种特殊的补充剂也是目前HS研究领域的热点，有着十分广阔的应用前景，可以进行更多、更深入的研究以探究其机制。
基金
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  • 上海市军民融合发展专项(2019-jmrh1-kj52)
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2021年第46卷第11期
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doi: 10.11855/j.issn.0577-7402.2021.11.14
  • 接收时间：2021-01-26
  • 首发时间：2025-12-19
  • 出版时间：2021-11-28
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  • 收稿日期：2021-01-26
  • 修回日期：2021-04-15
基金
Shanghai Military Civilian Integration Industry Development Project(2019-jmrh1-kj52)
上海市军民融合发展专项(2019-jmrh1-kj52)
作者信息
    1海军军医大学附属长海医院急诊科，上海 200433
    2海军军医大学附属长海医院麻醉学部，上海 200433
    3海军军医大学海军医学系卫生毒理学教研室，上海 200433

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Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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