運(yùn)動(dòng)、支氣管痙攣與哮喘——厘清、正視與平衡

石 月，陳佩杰，李 斐，朱小烽,2

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運(yùn)動(dòng)、支氣管痙攣與哮喘——厘清、正視與平衡

石 月1，陳佩杰1，李 斐1，朱小烽1,2

1. 上海體育學(xué)院, 上海 200438; 2. 嘉興學(xué)院 師范學(xué)院, 浙江 嘉興 314200

運(yùn)動(dòng)與支氣管痙攣及哮喘的研究已歷經(jīng)半個(gè)世紀(jì)，運(yùn)動(dòng)作為支氣管痙攣和哮喘的誘因早已得到共識。隨著全球哮喘人數(shù)及優(yōu)秀運(yùn)動(dòng)員群體哮喘發(fā)病率的持續(xù)增長，明確運(yùn)動(dòng)、支氣管痙攣和哮喘間的相互作用關(guān)系顯得尤為重要和迫切。研究從厘清運(yùn)動(dòng)誘發(fā)支氣管痙攣和運(yùn)動(dòng)誘發(fā)哮喘等相關(guān)概念出發(fā)，基于國內(nèi)外相關(guān)病理生理機(jī)制研究，對運(yùn)動(dòng)員群體好發(fā)哮喘的原因進(jìn)行總結(jié)，正視運(yùn)動(dòng)誘發(fā)支氣管痙攣和哮喘及運(yùn)動(dòng)改善哮喘的雙向作用；最終明晰高強(qiáng)度體力活動(dòng)對于哮喘患者的不利影響以及中等強(qiáng)度規(guī)律運(yùn)動(dòng)對于促進(jìn)機(jī)體整體健康的積極效應(yīng)。

運(yùn)動(dòng)誘發(fā)支氣管痙攣;運(yùn)動(dòng)誘發(fā)哮喘;運(yùn)動(dòng)員;哮喘;氣道炎癥;有氧運(yùn)動(dòng)

2017年，全球哮喘防治創(chuàng)議（ Global Initiative for Asthma，GINA）發(fā)布的哮喘更新指南[107]中對哮喘的定義為：哮喘（Asthma）是一種以慢性氣道炎癥為特點(diǎn)的異質(zhì)性疾病。主要特點(diǎn)包括多變的呼吸道癥狀（如喘息、氣促、胸悶及咳嗽）和可變的呼氣氣流受限。支氣管痙攣（Bronchospasm）是指細(xì)支氣管壁平滑肌持續(xù)收縮的一種功能狀態(tài)，是由于上呼吸道感染、過敏原及神經(jīng)刺激等因素造成的呼吸困難的現(xiàn)象[111]；支氣管痙攣是慢性支氣管炎、過敏反應(yīng)和哮喘疾病的典型癥狀，而并非獨(dú)立的疾病。流行病學(xué)研究報(bào)道[64]，2016年全球范圍內(nèi)哮喘人數(shù)占全世界總?cè)丝诘?.3%，全球近3億人遭受哮喘帶來的極大困擾，并以每10年20%～50%的比率上升，如此高比例的哮喘發(fā)病率給各國帶來了極大的醫(yī)療負(fù)擔(dān)。

運(yùn)動(dòng)誘發(fā)的支氣管痙攣和運(yùn)動(dòng)誘發(fā)的喘息在哮喘患者中很常見，預(yù)估40％～90％的哮喘患者有運(yùn)動(dòng)誘發(fā)癥狀[66,68]。GINA[107]指出：運(yùn)動(dòng)員，尤其是高水平運(yùn)動(dòng)員更易患多種呼吸道疾病，例如哮喘、呼吸道痙攣、過敏及非過敏性鼻炎等；同時(shí)，運(yùn)動(dòng)員哮喘發(fā)病率正呈逐年上升的趨勢[20,26,51]。全世界范圍內(nèi)，從事耐力性、對抗性、力量速度性項(xiàng)目的高水平運(yùn)動(dòng)員哮喘以及肺部功能異常情況發(fā)生率高，究其根源，與運(yùn)動(dòng)員長期高強(qiáng)度訓(xùn)練及污染物暴露關(guān)系密切。運(yùn)動(dòng)作為支氣管痙攣和哮喘的誘因并不能影響規(guī)律體育活動(dòng)對于改善肺功能、哮喘癥狀和提升機(jī)體整體健康的重要作用[79]。

本文從厘清運(yùn)動(dòng)誘發(fā)哮喘、運(yùn)動(dòng)誘發(fā)支氣管痙攣相關(guān)概念和關(guān)系出發(fā)，對運(yùn)動(dòng)誘發(fā)哮喘和支氣管痙攣及運(yùn)動(dòng)員高發(fā)哮喘的研究進(jìn)行系統(tǒng)歸納總結(jié)并闡明其病理生理機(jī)制；通過梳理體育活動(dòng)和身體鍛煉對于哮喘患者健康益處的研究，為普通人、哮喘患者和運(yùn)動(dòng)員如何更好地平衡運(yùn)動(dòng)和運(yùn)動(dòng)誘發(fā)性哮喘癥狀之間的關(guān)系提供指導(dǎo)建議。

1 運(yùn)動(dòng)誘發(fā)哮喘相關(guān)概念和關(guān)系的厘清

在過去幾十年運(yùn)動(dòng)與呼吸疾病的研究領(lǐng)域中，不乏有將運(yùn)動(dòng)誘發(fā)性支氣管痙攣（Exercise-induced bronchoconstriction/ bronchialspasm, EIB）和運(yùn)動(dòng)誘發(fā)性哮喘（Exercise-induced asthma, EIA）兩個(gè)術(shù)語混用以及將EIA和氣道高反應(yīng)性（Bronchial hyperresponsiveness， BHR）視為同一概念的現(xiàn)象。隨著普通人群和運(yùn)動(dòng)員患呼吸道疾病數(shù)量的增長，該領(lǐng)域獲得越來越多的關(guān)注度，將基本術(shù)語、概念及其相互關(guān)系的明確和厘清已成為近些年國內(nèi)外學(xué)者們努力倡導(dǎo)并著手實(shí)施的重要一步，這對于后續(xù)更精準(zhǔn)深入的研究和同行間更有效的學(xué)術(shù)交流有著重要的意義。本部分就哮喘、支氣管痙攣、氣道高反應(yīng)性、運(yùn)動(dòng)誘發(fā)性支氣管痙攣和運(yùn)動(dòng)誘發(fā)性哮喘進(jìn)行明確定義并指明其區(qū)別與聯(lián)系。

EIB是指在運(yùn)動(dòng)中或運(yùn)動(dòng)結(jié)束后氣道出現(xiàn)的暫時(shí)性狹窄，這常見于普通人群和運(yùn)動(dòng)員群體，但這些人群可能并非哮喘患者或并不具有任何呼吸道癥狀[15, 47, 60, 99]。EIA是指運(yùn)動(dòng)作為誘因致使哮喘發(fā)作，可見于非運(yùn)動(dòng)員職業(yè)的哮喘患者和運(yùn)動(dòng)員哮喘患者[104]。EIA是EIB和哮喘癥狀的結(jié)合。歐洲過敏及臨床免疫聯(lián)合工作小組和呼吸協(xié)會將EIA定義為劇烈運(yùn)動(dòng)后出現(xiàn)的哮喘癥狀，而EIB則更側(cè)重于在一次標(biāo)準(zhǔn)化的運(yùn)動(dòng)試驗(yàn)后，肺功能的減弱[28]（圖1）。BHR是指在應(yīng)對各種特異性或非特異性刺激時(shí)，氣道反應(yīng)性異常增高，支氣管平滑肌顯示出的更易收縮和收縮力更強(qiáng)的一種反應(yīng)狀態(tài)，表現(xiàn)為氣道平滑肌過早或過強(qiáng)的收縮反應(yīng)、支氣管痙攣和黏液腺體分泌的亢進(jìn)。BHR是哮喘患者氣道功能異常狀態(tài)的關(guān)鍵指標(biāo)，并可用于評價(jià)哮喘患者的病情和預(yù)后，在冬季項(xiàng)目和游泳項(xiàng)目運(yùn)動(dòng)員中尤為常見[60, 99]。

圖1 本研究幾個(gè)概念的相關(guān)關(guān)系模式圖

Figure1. Patterns of Correlation between Several Concepts

為更好的區(qū)分這幾個(gè)概念，基于人群、誘因和癥狀三個(gè)維度的劃分，可歸納得出下列結(jié)論（表1）：1）普通人群在運(yùn)動(dòng)過程中和運(yùn)動(dòng)結(jié)束后可能會出現(xiàn)EIB，常見于不適宜的劇烈運(yùn)動(dòng)或在特殊環(huán)境下運(yùn)動(dòng)，如寒冷、空氣污染嚴(yán)重或泳池水污染嚴(yán)重等情況；此外，普通人群也可能在其它非運(yùn)動(dòng)誘因的情況下出現(xiàn)支氣管痙攣，但不會出現(xiàn)哮喘、EIA和BHR癥狀；2）哮喘患者具備支氣管痙攣、哮喘和氣道高反應(yīng)性現(xiàn)象，而在運(yùn)動(dòng)過程中或運(yùn)動(dòng)結(jié)束后，部分會出現(xiàn)EIB和EIA，這是由于其誘發(fā)因素不同所導(dǎo)致的，運(yùn)動(dòng)不一定是所有哮喘患者哮喘發(fā)作的誘發(fā)因素；3）未診斷為哮喘的運(yùn)動(dòng)員與普通人群類似，在特定極端運(yùn)動(dòng)條件及除運(yùn)動(dòng)外的特殊情況下，部分會出現(xiàn)EIB和支氣管痙攣，但不會出現(xiàn)哮喘、EIA和BHR癥狀，需要注意的是職業(yè)運(yùn)動(dòng)員比普通人具有更高的哮喘患病率；4）已診斷為哮喘的運(yùn)動(dòng)員同時(shí)具備支氣管痙攣、哮喘、氣道高反應(yīng)性3種癥狀，并將運(yùn)動(dòng)視其主要誘因，出現(xiàn)EIA和EIB，這類人群長期的運(yùn)動(dòng)訓(xùn)練背景與哮喘的發(fā)生密不可分，但在哮喘病情有效控制及運(yùn)動(dòng)訓(xùn)練強(qiáng)度合理安排的情況下，EIA和EIB的發(fā)生率將大大降低。

表1 基于人群和誘因的癥狀發(fā)生情況一覽表

近期，國外諸多學(xué)者也就運(yùn)動(dòng)員哮喘群體進(jìn)行了類型劃分，最具代表性的是Mariana Couto 等[33]對來自葡萄牙和挪威的150名符合哮喘診斷標(biāo)準(zhǔn)的高水平運(yùn)動(dòng)員進(jìn)行的潛在類別分析。通過分析，他將運(yùn)動(dòng)員哮喘群體劃分為兩個(gè)集群：“過敏性哮喘”和“運(yùn)動(dòng)性哮喘”。前者是指哮喘伴隨著過敏性鼻炎和過敏性疾病的發(fā)生，以及呼出的一氧化氮水平增加；后者是指出現(xiàn)了運(yùn)動(dòng)誘發(fā)的呼吸道癥狀以及支氣管高反應(yīng)性現(xiàn)象但并不出現(xiàn)過敏特征（圖2），而特定的訓(xùn)練和比賽環(huán)境暴露則與“運(yùn)動(dòng)性哮喘”有關(guān)。此種群落分析有助于更進(jìn)一步認(rèn)識運(yùn)動(dòng)員哮喘群體，并且為部分運(yùn)動(dòng)員群體對常規(guī)哮喘藥物治療適應(yīng)不良的現(xiàn)象提供了新的提示：部分哮喘運(yùn)動(dòng)員的哮喘癥狀和病理生理機(jī)制有別于普通過敏性哮喘，如何針對性的診斷和控制該群體的哮喘癥狀有待深入研究和區(qū)別對待。

圖2 潛在集群分析中運(yùn)動(dòng)員呈現(xiàn)出每個(gè)變量的百分比[33]

Figure2. Percent of Athletes Presenting Each of the Variables Included for LCA[33]

2 正視運(yùn)動(dòng)誘因及運(yùn)動(dòng)員高發(fā)哮喘

2.1 運(yùn)動(dòng)誘發(fā)支氣管痙攣及哮喘

目前，大量研究已經(jīng)證實(shí)哮喘患者在運(yùn)動(dòng)后出現(xiàn)明顯支氣管痙攣現(xiàn)象；即使是未被診斷為哮喘的部分人群，在進(jìn)行中等強(qiáng)度運(yùn)動(dòng)后會出現(xiàn)輕微的支氣管痙攣[25]，而在劇烈運(yùn)動(dòng)后則出現(xiàn)肺功能明顯減弱，并顯示出發(fā)展為哮喘的危險(xiǎn)因素[106]。運(yùn)動(dòng)誘發(fā)哮喘癥狀的嚴(yán)重與否本質(zhì)上取決于氣道潛在炎癥水平的高低[34]。研究發(fā)現(xiàn)，運(yùn)動(dòng)可誘導(dǎo)絕大部分未合理采用抗炎治療的哮喘患者發(fā)病；對于已經(jīng)診斷為哮喘的人群，不同持續(xù)時(shí)間、運(yùn)動(dòng)強(qiáng)度和運(yùn)動(dòng)方式均能引起運(yùn)動(dòng)后不同程度的呼吸功能減弱和呼吸道阻力上升[34]。

綜上研究，維持6～36 min的中等至大強(qiáng)度運(yùn)動(dòng)均能引起哮喘患者FEV1值在運(yùn)動(dòng)中緩慢下降以及運(yùn)動(dòng)后顯著下降，呼吸道阻力持續(xù)上升。對普通個(gè)體而言，不適宜的運(yùn)動(dòng)強(qiáng)度均能引起支氣管出現(xiàn)急性收縮反應(yīng)。運(yùn)動(dòng)過程中由于交感神經(jīng)支配和攝氧量的需求，支氣管呈舒張狀態(tài)；而在運(yùn)動(dòng)結(jié)束后的恢復(fù)期，運(yùn)動(dòng)中支氣管所遭受的理化刺激加上迷走神經(jīng)控制增強(qiáng)，支氣管呈反射性的收縮，哮喘患者在此期間則更易出現(xiàn)支氣管痙攣和哮喘癥狀。

盡管如此，我們不能片面的得出哮喘患者不宜運(yùn)動(dòng)的錯(cuò)誤結(jié)論。以上研究均采用一次性中等及以上強(qiáng)度運(yùn)動(dòng)試驗(yàn)來觀察運(yùn)動(dòng)中和運(yùn)動(dòng)后氣道阻力和FEV1的情況，無法得知運(yùn)動(dòng)后經(jīng)較長時(shí)間恢復(fù)，氣道狀態(tài)是否得到改善，以及長期規(guī)律運(yùn)動(dòng)帶來的氣道適應(yīng)和肺功能改善情況。此外，哮喘是異質(zhì)性疾病，個(gè)體差別很大，哮喘患者之間氣道炎癥情況（是否為急性發(fā)作期）、用藥情況和發(fā)病誘因均不甚一致，不適合將整體呼吸機(jī)能測試的平均值來說明問題，更應(yīng)注重個(gè)體的、干預(yù)前后的呼吸機(jī)能變化趨勢，從大樣本量哮喘個(gè)體干預(yù)前后的變化趨勢中進(jìn)行歸類得出結(jié)論。

2.2 運(yùn)動(dòng)員群體高發(fā)哮喘的現(xiàn)狀

自20世紀(jì)80年代起，科研人員和醫(yī)生們就開始通過多種試驗(yàn)手段來評價(jià)運(yùn)動(dòng)員的氣道功能；到目前為止，已經(jīng)有大量的研究報(bào)道了不同年齡、不同項(xiàng)目、不同水平的運(yùn)動(dòng)員EIA和EIB的發(fā)病率（表2）。據(jù)推測，參加特定項(xiàng)目的運(yùn)動(dòng)員（如游泳和冬季項(xiàng)目），半數(shù)以上被診斷患有哮喘。由此，哮喘被列為高水平運(yùn)動(dòng)員中最為常見的慢性疾病之一[42]。

20世紀(jì)一項(xiàng)對659名意大利奧林匹克運(yùn)動(dòng)員進(jìn)行的4次橫斷面調(diào)查研究顯示：哮喘及支氣管痙攣的患病率為從2000年11.3%顯著增加至2008年的17.2%。肺部功能異常的現(xiàn)象同樣在我國高水平運(yùn)動(dòng)員中得以顯現(xiàn)。參加2006年多哈亞運(yùn)會的中國國家隊(duì)285名運(yùn)動(dòng)員中，48.1%的運(yùn)動(dòng)員存在肺通氣及小氣道功能的異常,其中以耐力項(xiàng)群和對抗性項(xiàng)群居多,肺功能異常情況的持續(xù)將直接造成氣道炎癥、支氣管痙攣以及哮喘的發(fā)生[1]。全世界范圍內(nèi)，高水平運(yùn)動(dòng)員群體高發(fā)哮喘以及肺部功能異常的情況，究其根源，是由于其長期進(jìn)行大強(qiáng)度、大運(yùn)動(dòng)量和長時(shí)間的訓(xùn)練造成的。此外，在競技體育殘酷競爭的現(xiàn)實(shí)下，各項(xiàng)比賽記錄被不斷打破，教練員與運(yùn)動(dòng)員力求突破人體極限，不斷增加訓(xùn)練量，導(dǎo)致過度運(yùn)動(dòng)的發(fā)生，這是造成運(yùn)動(dòng)員哮喘發(fā)病率逐年增高的主要原因。

普通人群和運(yùn)動(dòng)員發(fā)生EIA/EIB，其深層的發(fā)病機(jī)制有著一定的相似之處，但因?yàn)殚L期大強(qiáng)度訓(xùn)練和不良環(huán)境的暴露使得運(yùn)動(dòng)員哮喘患者存在特定的氣道炎癥反應(yīng)和氣道組織結(jié)構(gòu)，加之機(jī)體整體免疫機(jī)能和副交感神經(jīng)控制的區(qū)別，需要對這兩類人群的EIA/EIB予以區(qū)別看待。

表2 運(yùn)動(dòng)員群體中EIA/EIB發(fā)病率研究一覽表

注：CO2自主過度通氣（eucapnic voluntary hyperpnea，EVH）；呼氣峰值流速（peak expiratory flow rate，PEFR）；用力肺活量（forced vital capacity，F(xiàn)VC）；場地試驗(yàn)（field test，F(xiàn)T）；實(shí)驗(yàn)室運(yùn)動(dòng)試驗(yàn)（laboratory exercise test，LT）；特定項(xiàng)目運(yùn)動(dòng)激發(fā)試驗(yàn)（sport-specific exercise challenge，SS）；乙酰甲膽堿激發(fā)試驗(yàn)（methacholine provocative test，MT）；甘露醇激發(fā)試驗(yàn)（mannitol provocation test，MaT）；引起通氣功能指標(biāo)（如FEV1）下降20%的激發(fā)劑濃度（provocative concentration，PC20），單位為mg/L；引起通氣功能指標(biāo)（如FEV1）下降20%的激發(fā)劑劑量（provocative dose，PD20）。

2.3 EIA和EIB的病理生理機(jī)制

任何對人體某一器官系統(tǒng)的功能進(jìn)行研究時(shí)，都不能將其從整體中割裂，而是時(shí)刻將人作為一個(gè)設(shè)計(jì)精良的整體來看待，運(yùn)動(dòng)對于呼吸道的控制亦是如此。神經(jīng)、內(nèi)分泌和免疫系統(tǒng)的相互作用雖不明顯但是貫穿始終。

本部分基于對運(yùn)動(dòng)中神經(jīng)、內(nèi)分泌和免疫系統(tǒng)相互調(diào)節(jié)的基礎(chǔ)上，從5種假說出發(fā)，探討EIA/EIB病理生理機(jī)制（圖3）。幾種假說在解釋EIA和EIB的發(fā)生過程中有著不同的側(cè)重點(diǎn)，但彼此間存在相互聯(lián)系。有關(guān)哮喘患者和正常人在運(yùn)動(dòng)過程中氣道阻力和肺功能變化的詳細(xì)描述及正常人運(yùn)動(dòng)過程中交感神經(jīng)和副交感神經(jīng)的相互平衡作用可分別參照Robert W. Gotshall[44]和James P. Fisher等[41]作的綜述。

圖3 普通人群和運(yùn)動(dòng)員EIA/EIB病理生理機(jī)制示意圖

Figure3. Diagram of Pathophysiological Mechanism of EIA/EIB in General Population and Athletes

2.3.1 超滲透壓假說

20世紀(jì)80年代，Anderson等人提出了“超滲透壓假說”[3, 5]。進(jìn)行中等強(qiáng)度運(yùn)動(dòng)時(shí)，吸入的干燥氣體可在近端支氣管內(nèi)進(jìn)行加溫加濕處理，這些氣道表面的液體不超過1 ml；當(dāng)以60 L/min通氣量進(jìn)行呼吸時(shí)，氣道表面30%的水分需要用來濕潤這些干燥氣體[2]。隨著運(yùn)動(dòng)強(qiáng)度的上升，以及吸入更多的干冷氣體，需要更多的氣道水分參與此過程，水分的蒸發(fā)濃縮導(dǎo)致Na+、Cl-、Ca+和K+離子濃度的上升，從而造成粘膜纖毛清除率的降低及氣道粘膜表面液體的高滲[3,8]。這種滲透梯度刺激肥大細(xì)胞釋放如組胺、白三烯和前列腺素等炎癥介質(zhì)[37]。其中，白三烯可激活特異性受體并引起氣道平滑肌收縮和粘液分泌[6, 53]，從而導(dǎo)致氣道狹窄以及出現(xiàn)運(yùn)動(dòng)性支氣管痙攣，吸入甘露醇試驗(yàn)來診斷氣道高反應(yīng)性支持了該假說的成立[22]。

2.3.2 氣道重加溫假說

20世紀(jì)80年代末、90年代初，McFadden等[54-56]提出了運(yùn)動(dòng)后氣道的重加溫是引發(fā)運(yùn)動(dòng)性支氣管痙攣的原因。根據(jù)此假說，運(yùn)動(dòng)過程中伴隨的高通氣量使氣道上皮細(xì)胞表面冷卻。并且在運(yùn)動(dòng)過程中，尤其是運(yùn)動(dòng)結(jié)束后，氣道開始了重加溫的過程，這是繼之前氣道冷卻后的階段。復(fù)溫過程引起繼發(fā)性充血，毛細(xì)血管的滲透性增加，導(dǎo)致液體從毛細(xì)血管滲漏到粘膜下層，氣道水腫，肥大細(xì)胞遭受刺激釋放炎癥介質(zhì)，引發(fā)氣道炎癥和支氣管收縮[4]。較高的氣道血管通透性被證實(shí)與哮喘患者運(yùn)動(dòng)性支氣管痙攣嚴(yán)重程度直接相關(guān)[57]。研究發(fā)現(xiàn)，競技游泳運(yùn)動(dòng)員，無論其是否患有哮喘，其氣道微血管通透性與哮喘患者相似，而肺功能和氣道高反應(yīng)性并沒有相關(guān)關(guān)系[74]。此外，氣道的冷卻反射性刺激副交感神經(jīng)，導(dǎo)致迷走神經(jīng)作用增強(qiáng)引起支氣管痙攣；最初引起支氣管靜脈的反射性血管收縮以起到保溫作用，隨后在運(yùn)動(dòng)結(jié)束后次級氣道通過支氣管充血、水腫以及進(jìn)一步縮小氣道來恢復(fù)溫度[27]。

2.3.3 上皮細(xì)胞損傷及氣道重塑假說

Anderson等[7]提出上皮細(xì)胞損傷是造成優(yōu)秀運(yùn)動(dòng)員運(yùn)動(dòng)性支氣管痙攣的原因。最初是馬拉松運(yùn)動(dòng)員在耐力訓(xùn)練后，發(fā)生氣道上皮細(xì)胞損傷[30]，支持此假說的證據(jù)在于氣道損傷標(biāo)志物的血清克拉氏細(xì)胞蛋白（Clara cell protein 16，CC16）及痰液中支氣管上皮細(xì)胞的發(fā)現(xiàn)[89]。急性劇烈運(yùn)動(dòng)后，尿液[13, 83]和血清[24, 30]中CC16含量增多，此現(xiàn)象也同樣出現(xiàn)在自主過度通氣的運(yùn)動(dòng)員中[14]。此外，肺刺激物三氯胺暴露也可使CC16表達(dá)上升[23]，提示運(yùn)動(dòng)伴隨的氣道理化刺激和污染物均能造成上皮細(xì)胞損傷。除CC16外，冬季項(xiàng)目和游泳項(xiàng)目運(yùn)動(dòng)員痰液中出現(xiàn)大量的氣道上皮細(xì)胞也證明了運(yùn)動(dòng)對于氣道上皮造成損傷。粘蛋白分泌細(xì)胞替代纖毛上皮細(xì)胞是氣道上皮細(xì)胞損傷的后果之一，運(yùn)動(dòng)員顯示出比健康成人和哮喘患者更多的杯狀細(xì)胞增生以及更高水平的粘蛋白表達(dá)[18]。損傷的氣道上皮細(xì)胞導(dǎo)致氣道中損傷相關(guān)分子模式（Damage Associated molecular patterns，DAMPs）的增多[89]，繼而引發(fā)一系列炎癥反應(yīng)，這些物質(zhì)的長期暴露可導(dǎo)致平滑肌收縮特性的改變，使其對支氣管收縮介質(zhì)更為敏感[37]。

氣道重塑是氣道上皮細(xì)胞損傷并呈持續(xù)炎癥的結(jié)果，也是哮喘的特征性變化，這種結(jié)構(gòu)的改變包括上皮下纖維化、氣道平滑肌增生肥大、杯狀細(xì)胞和黏膜腺體增生及血管增殖等。游泳運(yùn)動(dòng)員氣道中可觀察到較大的黏膜下I型和III型膠原蛋白表達(dá)和腱生蛋白沉積[18]；優(yōu)秀的冬季項(xiàng)目運(yùn)動(dòng)員氣道中，也觀察到比正常人更多的腱生蛋白厚度和炎癥細(xì)胞數(shù)目[58]。

2.3.4 氣道炎癥假說

氣道炎癥是運(yùn)動(dòng)性支氣管痙攣和哮喘發(fā)生發(fā)展的關(guān)鍵，也是所有假說最核心的部分。哮喘的經(jīng)典發(fā)病機(jī)制是以嗜酸性粒細(xì)胞和肥大細(xì)胞浸潤為主，Th2型炎癥反應(yīng)增強(qiáng)的氣道炎癥過程。成人競技游泳運(yùn)動(dòng)員支氣管活檢觀察到嗜酸性粒細(xì)胞和肥大細(xì)胞數(shù)量的增多[18]，并且哮喘患者運(yùn)動(dòng)試驗(yàn)后的尿液[75,82]和痰液中檢測出白細(xì)胞三烯E4或前列腺素D2的代謝物（肥大細(xì)胞介質(zhì)釋放的標(biāo)志物），證實(shí)了經(jīng)典哮喘氣道炎癥反應(yīng)在EIA/EIB病理機(jī)制中的作用[46,75, 82]。

新近研究發(fā)現(xiàn)，運(yùn)動(dòng)員哮喘患者誘導(dǎo)痰中存在大量中性粒細(xì)胞[16, 31]，白細(xì)胞介素17A(Interleukin 17A，IL-17A)細(xì)胞因子高表達(dá)以及在耐力項(xiàng)目運(yùn)動(dòng)員外周血中Th17細(xì)胞顯著增加，Treg細(xì)胞持續(xù)下降[80]。此外，對運(yùn)動(dòng)員人群氣道炎癥的大量研究顯示，耐力性項(xiàng)目運(yùn)動(dòng)員（游泳，越野滑雪、馬拉松）氣道中的中性細(xì)胞數(shù)量，IL-8、IL-1β、IL-17A、IL-6、腫瘤壞死因子（Tumor Necrosis Factor，TNF）-α均顯著高于普通人群[96, 101]，與中性粒細(xì)胞性哮喘病人氣道中的炎癥情況高度相似，并且運(yùn)動(dòng)員無論是在訓(xùn)練后即刻還是在休息期間，氣道炎癥水平均沒有明顯差異；提示，急性劇烈運(yùn)動(dòng)可以提高氣道炎癥水平，長期高強(qiáng)度訓(xùn)練的運(yùn)動(dòng)員在遭受反復(fù)運(yùn)動(dòng)刺激后，形成了氣道慢性炎癥。盡管尚未有明確的研究證明患哮喘的運(yùn)動(dòng)員是屬于中性粒細(xì)胞性哮喘，但可以推測，中性粒細(xì)胞以及Th17型炎癥反應(yīng)在運(yùn)動(dòng)致使哮喘發(fā)病進(jìn)程中起重要作用。

除運(yùn)動(dòng)造成氣道本身炎癥外，近些年還出現(xiàn)了神經(jīng)源性氣道炎癥的觀點(diǎn)[72]。研究發(fā)現(xiàn)，劇烈運(yùn)動(dòng)可引起循環(huán)神經(jīng)源性炎癥刺激因子P物質(zhì)表達(dá)升高[63]，這可能是由于PPT-1基因上調(diào)導(dǎo)致的結(jié)果，PPT-1基因是P物質(zhì)和NK-1受體的來源。Teixeira等[103]系統(tǒng)地比較了P物質(zhì)和游泳應(yīng)激誘導(dǎo)小鼠產(chǎn)生的行為和免疫學(xué)效應(yīng)，并研究了NK-1受體參與調(diào)節(jié)這些效應(yīng)的作用。結(jié)果顯示，小鼠體內(nèi)注射P物質(zhì)可表現(xiàn)出類似于游泳行為的應(yīng)激效應(yīng)，而NK-1受體的拮抗劑則抑制了游泳應(yīng)激效應(yīng)[103]。然而在人類中，神經(jīng)源性氣道炎癥在EIA和EIB的發(fā)病機(jī)制中的作用一直沒有得到充分研究。

2.3.5 神經(jīng)元激活假說

已有研究證實(shí)，反復(fù)大強(qiáng)度訓(xùn)練可以使迷走神經(jīng)占據(jù)支配地位，這不僅可以造成優(yōu)秀運(yùn)動(dòng)員靜息心動(dòng)徐緩，還可引起支氣管肌緊張，因而支氣管痙攣的易感性隨之增加[72]。越來越多的研究論證了運(yùn)動(dòng)引起的自主神經(jīng)功能異常可支持此假說成立[40]。

縱觀50多年的研究歷史，關(guān)于高水平運(yùn)動(dòng)員患哮喘和支氣管痙攣的發(fā)病機(jī)制探究主要集中于：“超滲透壓”、“氣道重加溫”、“上皮細(xì)胞損傷及氣道重塑”、“氣道炎癥”和“神經(jīng)元激活”這5個(gè)方面[20]。將這些不同角度和不同側(cè)重點(diǎn)進(jìn)行的研究結(jié)論和觀點(diǎn)相互串聯(lián)，得出較為完整、一致的發(fā)病機(jī)理是：高水平優(yōu)秀運(yùn)動(dòng)員在經(jīng)常性劇烈運(yùn)動(dòng)的過程中，每分通氣量急劇上升，大量外界氣體進(jìn)入呼吸道，造成呼吸道熱量、水分的丟失，同時(shí)動(dòng)員小氣道參與加溫氣體，氣道黏膜層的干燥和氣道表面液體滲透壓的增高使氣道上皮細(xì)胞損傷，天然免疫細(xì)胞大量動(dòng)員，粘液及炎性介質(zhì)分泌增加，血管通透性增加，微血管滲漏和血漿物質(zhì)滲出使氣道平滑肌反應(yīng)性增高；炎癥反應(yīng)持續(xù)發(fā)展使上皮下纖維化、氣道平滑肌增生肥大、杯狀細(xì)胞和黏膜腺體增生及血管增殖，氣道縮窄、氣流受限，引發(fā)支氣管痙攣。此外，長期劇烈運(yùn)動(dòng)造成迷走神經(jīng)控制作用增強(qiáng)及系統(tǒng)免疫受到短暫抑制，加之過多污染物和變應(yīng)原進(jìn)入氣道，極大增加支氣管痙攣和過敏性呼吸道疾病的發(fā)生率[65,78,85,86]。這些研究可以給出提示，高水平運(yùn)動(dòng)員以及其他相關(guān)污染環(huán)境暴露的職業(yè)人群進(jìn)行氣道保護(hù)的預(yù)防性策略是非常必要的。

盡管運(yùn)動(dòng)員群體具備較高的EIA/EIB的發(fā)病風(fēng)險(xiǎn)，但并不因此影響競技能力的發(fā)揮。在運(yùn)動(dòng)員哮喘患者癥狀得到很好的控制后，仍能參加同級別的奧林匹克及其它頂級水平的國際比賽。甚至有研究報(bào)道，患哮喘的運(yùn)動(dòng)員相比于非哮喘運(yùn)動(dòng)員能贏得更多的金牌[42]，這也有待進(jìn)一步論證。

3 規(guī)律適度運(yùn)動(dòng)對健康的益處及與EIA/EIB的平衡

運(yùn)動(dòng)可以改善哮喘并且提高生活質(zhì)量，這是當(dāng)前科學(xué)家們達(dá)成的共識[91]。盡管多數(shù)人都能夠意識到運(yùn)動(dòng)對于健康的益處，然而，醫(yī)生們還尚未將足量的身體活動(dòng)作為重要的處方之一，加之哮喘患者不宜運(yùn)動(dòng)的傳統(tǒng)片面觀點(diǎn)，讓大部分哮喘患者對運(yùn)動(dòng)望而卻步。

Philipp等[38]對包含599名哮喘患者的17項(xiàng)研究進(jìn)行了Meta分析，結(jié)果顯示：在哮喘患者無呼吸道癥狀的時(shí)期內(nèi)，運(yùn)動(dòng)可以顯著改善FEV1和運(yùn)動(dòng)能力，BHR顯示出輕微改善。與對照組相比，運(yùn)動(dòng)可以顯著改善生活質(zhì)量（17%）、BHR（53%）、EIB（9%）和FEV1(3%)。Avallone等[10]也就2013年以前的相關(guān)實(shí)驗(yàn)性文章進(jìn)行了綜述，總結(jié)出的結(jié)論為：哮喘患者相比于普通人更少地參與體育活動(dòng)，缺乏體力活動(dòng)的哮喘患者顯示出對健康的消極影響，規(guī)律有氧運(yùn)動(dòng)可以改善哮喘癥狀的管理、肺功能及心理健康。

一項(xiàng)隨機(jī)對照試驗(yàn)顯示[88]，持續(xù)12周、每周3次的有氧及抗阻訓(xùn)練對于改善肥胖哮喘患者氣道炎癥反應(yīng)有著良性作用。西方國家靜坐少動(dòng)及超重、肥胖的人群一直處于較高水平[9]，研究顯示，體重增加和肥胖使入侵性哮喘的發(fā)病率增加近一倍[71]。并且肥胖人群在運(yùn)動(dòng)過程中出現(xiàn)的類似哮喘癥狀的氣喘、呼吸困難等，可能是由于缺乏體力活動(dòng)或其它上呼吸道結(jié)構(gòu)異常導(dǎo)致的，要予以區(qū)別對待。

臨床試驗(yàn)發(fā)現(xiàn)，規(guī)律運(yùn)動(dòng)可起到抵抗免疫球蛋白E（Immunoglobulin E，IgE）的作用，降低患哮喘兒童總的和抗原特異性IgE的水平[73]。無論是經(jīng)過3個(gè)月有氧訓(xùn)練或是一次游泳課訓(xùn)練，經(jīng)運(yùn)動(dòng)或乙酰甲膽堿試驗(yàn)測得的兒童支氣管反應(yīng)性均下降。除此之外，在患哮喘的成年人中，3個(gè)月的有氧訓(xùn)練降低了痰液嗜酸性粒細(xì)胞以及呼出的一氧化氮的水平[39, 69, 109]。規(guī)律運(yùn)動(dòng)同樣影響了氣道的重塑[92]，在哮喘動(dòng)物模型中，有氧運(yùn)動(dòng)訓(xùn)練增加了抗炎癥細(xì)胞因子，降低了炎癥介質(zhì)的表達(dá)并恢復(fù)氣道重塑[93]。

此外，研究顯示，無論是兒童還是成年人，在哮喘疾病沒有得到很好的控制時(shí)，身體鍛煉也不會引起疾病的加重[73, 105]。相反，積極鼓勵(lì)哮喘兒童們參加有氧鍛煉可有效地緩解因疾病造成的焦慮，非常適用具有較高社會心理困擾的哮喘患者及家庭[70, 90]。參與體育活動(dòng)也可促進(jìn)孩子正常的心理發(fā)育及神經(jīng)肌肉的協(xié)調(diào)性[61, 62]，推薦兒童和青少年每天參加至少持續(xù)60 min的身體活動(dòng)[21]。美國運(yùn)動(dòng)醫(yī)學(xué)學(xué)會（American College of Medicine, ACSM）和美國疾病控制及預(yù)防中心也就成年哮喘患者有氧、無氧和柔韌性運(yùn)動(dòng)處方的具體內(nèi)容以及相關(guān)注意事項(xiàng)形成了推薦建議（表3）。

表3 成年哮喘患者運(yùn)動(dòng)處方（FITT）建議[81,95]

“生物多樣性假說”觀點(diǎn)認(rèn)為，運(yùn)動(dòng)可增加環(huán)境基因組和人類微生物基因組之間更大的相互作用機(jī)會[32]。城市化過程和久坐不動(dòng)的生活方式導(dǎo)致了生物多樣性的喪失，較少的人類微生物群（失調(diào)）和免疫功能障礙（耐受性差），最終致使臨床疾病發(fā)生[45]。對健康和患病個(gè)體的宏基因組學(xué)和其他研究表明，生物多樣性減少以及腸道和皮膚微生物群組成的改變與各種炎癥狀態(tài)有關(guān)，包括哮喘，過敏，炎癥性腸病，I型糖尿病和肥胖癥[45]。如果哮喘和過敏人群能夠維持足夠的身體活動(dòng)水平，特別是在自然生物多樣性的環(huán)境下，他們將不太可能遭受與久坐生活方式相關(guān)的不良健康事件，如心臟病、中風(fēng)或糖尿病等，并且可以改善其哮喘癥狀。

綜上研究內(nèi)容，身體活動(dòng)與EIA和EIB發(fā)病率的關(guān)系總體呈現(xiàn)出劑量依賴型關(guān)系，A. Moreira 和 L. Delgado提出的“U”型曲線對其作出很好的解釋[43]：中等強(qiáng)度身體活動(dòng)有著最低的哮喘發(fā)病率，隨著運(yùn)動(dòng)強(qiáng)度的上升，哮喘發(fā)病率隨之提高（圖4），這與規(guī)律中等強(qiáng)度運(yùn)動(dòng)所帶來的整體健康效益密不可分。

圖4 身體活動(dòng)與哮喘發(fā)生率間的劑量依賴性曲線圖[43]

Figure4. Suggested Dose-response Relationship between Physical Activity and Asthma Risk[43]

4 結(jié)語

2017版GINA[107]中，“控制哮喘癥狀和減少未來發(fā)病率——非藥物干預(yù)”這部分中列出了身體活動(dòng)這一項(xiàng)，并作出了如下描述：鼓勵(lì)哮喘患者進(jìn)行常規(guī)體育活動(dòng)，以獲得一般健康益處；對于運(yùn)動(dòng)誘發(fā)性支氣管痙攣的預(yù)防和管理提供建議；規(guī)律的體力活動(dòng)可改善心肺功能，但目前沒有明確其對肺功能和哮喘癥狀的具體益處（除患哮喘的年輕人可通過游泳運(yùn)動(dòng)獲得益處外）；目前無證據(jù)證明哪種類型的身體活動(dòng)是最優(yōu)的，故無法推薦最合適的鍛煉方式。

總的說來，哮喘控制驅(qū)使哮喘管理，探究運(yùn)動(dòng)的益處會對制定新的哮喘管理策略產(chǎn)生影響。普通哮喘患者，在哮喘癥狀得到很好控制時(shí)，根據(jù)自身體能狀況，積極進(jìn)行規(guī)律的中等強(qiáng)度體育鍛煉很有必要；競技運(yùn)動(dòng)員，根據(jù)其所從事的運(yùn)動(dòng)項(xiàng)目，應(yīng)就哮喘發(fā)展的癥狀以及氣道高反應(yīng)性進(jìn)行持續(xù)監(jiān)測，并且盡可能減少極端環(huán)境和污染源暴露，做好氣道防護(hù)；同時(shí)，早期診斷和系統(tǒng)抗炎治療可以使運(yùn)動(dòng)員繼續(xù)參與運(yùn)動(dòng)并不會對其競技表現(xiàn)造成負(fù)面影響[20,27]。未來，對于運(yùn)動(dòng)誘發(fā)性支氣管痙攣和哮喘的深層機(jī)制，包括遺傳易感性、神經(jīng)內(nèi)分泌調(diào)節(jié)及Th2/Th17免疫調(diào)節(jié)等需要更為深入的研究。此外，研究并設(shè)計(jì)多種治療性質(zhì)的身體活動(dòng)干預(yù)處方，以配合當(dāng)前的藥物治療方案也是當(dāng)下對運(yùn)動(dòng)科學(xué)和呼吸醫(yī)學(xué)領(lǐng)域人才交叉合作提出的新的課題。

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Exercise, Bronchospasm and Asthma —— Clarifying, Facing and Balancing

SHI Yue1, CHEN Pei-jie1, LI Fei1, ZHU Xiao-feng1, 2

1. Shanghai University of Sport, Shanghai 200438, China; 2. Jiaxing University, Jiaxing 314200, China.

Exercise, bronchospasm and asthma have been studied for half a century. Exercise has long been recognized as a trigger for bronchospasm and asthma. With the global number of asthma and the number of elite athletes’ asthma incidence continued to increase, it is of utmost importance and urgency to clarify the interaction between exercise, bronchospasm and asthma. In this paper, based on the related concepts of exercise-induced bronchospasm and asthma, the causes of asthma in athletes are summarized according to the relevant pathological and physiological mechanisms at home and abroad. The main purpose is to face up to the bidirectional effects of exercise-induced bronchospasm and asthma, and exercise to improve asthma. Finally, the adverse effects of high intensive exercise on asthma patients and the positive effects of moderate intensive regular exercise on overall health are clarified.

G804.5

A

1000-677X(2018)08-0075-11

10.16469/j.css.201808009

2018-04-26；

2018-08-14

上海市教育發(fā)展基金會和上海市教育委員會“晨光計(jì)劃”資助項(xiàng)目（16CGB29）。

石月,女,講師,在讀博士研究生,主要研究方向?yàn)檫\(yùn)動(dòng)免疫學(xué),E-mail:shiyue910@sina.com。