楊 卿，顏春松

·新進(jìn)展·

急性呼吸窘迫綜合征異質(zhì)性的研究進(jìn)展

楊 卿，顏春松*

急性呼吸窘迫綜合征是一種異質(zhì)性綜合征，在病因、發(fā)病機(jī)制、臨床表現(xiàn)、治療、預(yù)后等方面存在差異，根據(jù)這些差異可將其分為不同表型，以指導(dǎo)臨床治療和判斷預(yù)后。本文旨在對(duì)急性呼吸窘迫綜合征的異質(zhì)性及表型的研究進(jìn)展進(jìn)行綜述。

呼吸窘迫綜合征，成人；異質(zhì)性；表型

楊卿，顏春松.急性呼吸窘迫綜合征異質(zhì)性的研究進(jìn)展[J].中國(guó)全科醫(yī)學(xué)，2017，20(13)：1648-1653.[www.chinagp.net]

YANG Q,YAN C S.Research progress on heterogeneity of acute respiratory distress syndrome[J].Chinese General Practice，2017，20(13)：1648-1653.

1967年ASHBAUGH等[1]首次觀察到在272例接受呼吸支持的成年患者中有12例患者對(duì)常規(guī)治療無(wú)效，其均出現(xiàn)一種呼吸窘迫綜合征，臨床表現(xiàn)為呼吸困難、呼吸急促、發(fā)紺，且對(duì)氧療無(wú)效，肺順應(yīng)性下降，胸部X線片提示彌漫性肺泡滲出。這種呼吸窘迫綜合征的臨床表現(xiàn)、生理及病理進(jìn)程均與新生兒呼吸窘迫綜合征(透明膜病)極其相似，且均在原發(fā)病后1～96 h出現(xiàn)，故將其稱為成人急性呼吸窘迫(acute respiratory distress in adults)。1971年P(guān)ETTY等[2]將這種呼吸窘迫綜合征命名為成人呼吸窘迫綜合征(adult respiratory distress syndrome，ARDS)。1985年ARDS的病死率仍高達(dá)60%以上[3]，為明確其定義、更好地理解其發(fā)病機(jī)制并評(píng)估治療，1988年MURRAY等[4]提出了肺損傷評(píng)分，但之后ARDS的病死率仍為10%～90%，波動(dòng)較大。1994年美歐聯(lián)席會(huì)議(AECC)提出了急性肺損傷(ALI)/ARDS的定義和診斷標(biāo)準(zhǔn)，并將成人呼吸窘迫綜合征更名為急性呼吸窘迫綜合征(acute respiratory distress syndrome，ARDS)，指出ALI是一種炎性反應(yīng)和肺通透性增高的綜合征，這種通透性增高不能用左心房和/或肺毛細(xì)血管高壓解釋，而ARDS是ALI的嚴(yán)重階段[5]。同時(shí)，該會(huì)議認(rèn)為ARDS的異質(zhì)性也是影響患者預(yù)后的因素之一[5]。但廣泛應(yīng)用結(jié)果顯示，與彌漫性肺泡損傷的尸檢病理結(jié)果相比，AECC的診斷標(biāo)準(zhǔn)僅有中等靈敏度和特異度[6]，且診斷準(zhǔn)確性也并不高[7-8]。因此，2011年在歐洲重癥醫(yī)學(xué)學(xué)會(huì)的倡議下，美國(guó)胸科學(xué)會(huì)和重癥醫(yī)學(xué)學(xué)會(huì)共同參與修訂了新的診斷標(biāo)準(zhǔn)——ARDS柏林標(biāo)準(zhǔn)[9]。雖然ARDS的診斷和治療取得了長(zhǎng)足進(jìn)展，但其死亡率仍高達(dá)38.1%～42.1%，尤其是重度ARDS的院內(nèi)病死率高達(dá)41.9%～50.4%[10]。重要原因之一就是其病因、發(fā)病機(jī)制錯(cuò)綜復(fù)雜，臨床表現(xiàn)、治療、預(yù)后等諸多方面存在差異，具有異質(zhì)性。根據(jù)ARDS的異質(zhì)性可將其分為不同表型，本文旨在對(duì)其異質(zhì)性及表型的研究進(jìn)展進(jìn)行綜述，以期為更好地理解ARDS的發(fā)病機(jī)制、提高臨床治療水平提供新思路。

1 病因表型

1998年GATTINONI等[11]發(fā)現(xiàn)，肺部感染與腹部疾病導(dǎo)致的ARDS病理改變和對(duì)呼氣末正壓通氣(PEEP)的治療反應(yīng)并不相同，并根據(jù)這一現(xiàn)象將ARDS分為由肺部疾病所致的肺內(nèi)源性ARDS(primarily from pulmonary diseases，ARDSp)和肺外疾病所致的肺外源性ARDS(primarily from extra-pulmonary diseases，ARDSexp)。進(jìn)一步的研究發(fā)現(xiàn)，ARDSp和ARDSexp在發(fā)病機(jī)制、病理及臨床表現(xiàn)等方面存在一定差異。

1.1 病理表現(xiàn) ARDSexp的內(nèi)皮損傷可能更明顯，而肺上皮細(xì)胞相對(duì)完整，透明膜較薄且均勻連續(xù)分布[12]；ARDSp的上皮損傷、肺泡塌陷、纖維蛋白沉積較明顯[13]，透明膜較厚且易中斷[12]。ARDS動(dòng)物模型也提示，ARDSp造成肺上皮細(xì)胞層破壞、透明膜形成及中性粒細(xì)胞凋亡，ARDSexp則以肺間質(zhì)水腫為主、肺泡腔結(jié)構(gòu)相對(duì)完整[14]；ARDSp肺泡內(nèi)膠原蛋白持續(xù)增加可達(dá)8周，但ARDSexp膠原蛋白沉積可被迅速逆轉(zhuǎn)[15]。這可能是PEEP對(duì)ARDSp的治療效果不如ARDSexp的病理基礎(chǔ)。

1.2 影像學(xué)表現(xiàn) 在胸部影像學(xué)表現(xiàn)上，二者間也存在差異。胸部CT檢查提示，ARDSp的磨玻璃影與肺實(shí)變范圍相當(dāng)，且肺實(shí)變不對(duì)稱；ARDSexp的雙肺磨玻璃影較肺實(shí)變更加明顯，且磨玻璃影對(duì)稱，多分布在近肺門的中央?yún)^(qū)[16]。二者普遍存在胸腔積液、支氣管充氣征。但DESAI等[17]指出，雖然二者的CT表現(xiàn)存在差異，但在某些情況下對(duì)ARDSp胸部CT檢查的識(shí)別主要基于其表現(xiàn)是否典型，而不是基于某個(gè)影像學(xué)特征。

1.3 呼吸力學(xué)及治療反應(yīng) 二者在呼吸力學(xué)及治療反應(yīng)方面也存在差異。GATTINONI等[11]通過(guò)研究發(fā)現(xiàn)，ARDSp患者肺彈性阻力升高，并隨PEEP的增加而增加；而ARDSexp患者肺和胸壁彈性阻力均升高，并隨PEEP的增加而減小。LIM等[18]和PELOSI等[19]的研究結(jié)果表明，PEEP對(duì)ARDSexp的治療效果優(yōu)于ARDSp，推測(cè)二者對(duì)PEEP的不同反應(yīng)可能是因?yàn)锳RDSexp主要表現(xiàn)為肺泡萎陷(肺泡易于復(fù)張)，而ARDSp則主要表現(xiàn)為肺實(shí)變(肺泡不易于復(fù)張)。LIM等[18]在對(duì)47例ARDS患者(31例ARDSp、16例ARDSexp)采用俯臥位通氣方式治療時(shí)，發(fā)現(xiàn)ARDSexp患者的氧合指數(shù)和胸部X線片的改善明顯優(yōu)于ARDSp患者，這與PELOSI等[19]的研究結(jié)果一致。導(dǎo)致二者差異的原因可能為：ARDSexp的主要改變是肺萎陷和不張導(dǎo)致的低氧血癥，俯臥位通氣有助于肺內(nèi)通氣的重新分布和局部經(jīng)肺壓的改變，這均會(huì)對(duì)改善氧合指數(shù)起到迅速而積極的作用；ARDSp以肺實(shí)變?yōu)橹?，俯臥位通氣對(duì)肺內(nèi)氣體重新分布所起的作用較小[20]。

1.4 患者死亡率 多項(xiàng)研究結(jié)果顯示，ARDSp的死亡率高于ARDSexp[21-23]。但2008年一項(xiàng)納入了34個(gè)研究共4 311例ARDS患者的meta分析結(jié)果顯示，二者病死率間無(wú)差異，這可能是因?yàn)榉治鲞^(guò)程中將各研究間的異質(zhì)性及諸多重要研究均排除在外所致[24]。

1.5 生物標(biāo)志物 二者的生物學(xué)標(biāo)志物可能也存在差異。CALFEE等[25]的研究結(jié)果顯示，ARDSp患者的血漿肺上皮細(xì)胞損傷標(biāo)志物肺表面活性物質(zhì)相關(guān)蛋白-D(SP-D)的水平明顯高于ARDSexp患者，而內(nèi)皮細(xì)胞損傷標(biāo)志物血管生成素-2(Ang-2)、血管性血友病因子(vWF)抗原和炎性標(biāo)志物白介素6(IL-6)、白介素8(IL-8)明顯低于ARDSexp患者。提示ARDSp早期可能以肺泡上皮細(xì)胞損傷為主，而ARDSexp早期可能以血管內(nèi)皮細(xì)胞損傷為主。這可能為ARDS的治療提供了新思路，如ARDSexp早期可以保護(hù)毛細(xì)血管內(nèi)皮細(xì)胞為主，血管生成素-1(Ang-1)的變異體(MAT.Ang-1)、酪氨酸激酶受體2(Tie-2)的激動(dòng)劑、1-磷脂-鞘氨醇及其類似物等可減輕毛細(xì)血管滲漏，保護(hù)內(nèi)皮屏障[26-29]；而ARDSp早期可以保護(hù)肺泡上皮細(xì)胞為主，研究表明18∶1/18∶1二油酰磷脂酰甘油和角化細(xì)胞生長(zhǎng)因子可保護(hù)肺泡上皮細(xì)胞，減輕肺損傷的肺水腫表現(xiàn)[30-31]。

1.6 遺傳學(xué)表現(xiàn) 另外，ARDSp和ARDSexp的發(fā)生與遺傳學(xué)也存在一定關(guān)系。研究發(fā)現(xiàn)，單核苷酸多態(tài)性rs1190286(POPDC3基因)、腫瘤壞死因子的-308A等位基因可能會(huì)降低肺部疾病發(fā)展成為ARDS的風(fēng)險(xiǎn)[32]；腫瘤壞死因子的TNFB22等位基因可能降低肺外疾病發(fā)展成為ARDS的風(fēng)險(xiǎn)[33]，而單核苷酸多態(tài)性rs324420 (FAAT基因)可能增加肺外疾病發(fā)展成為ARDS的風(fēng)險(xiǎn)[32]。

2 創(chuàng)傷表型

2007年CALFEE等[34]納入了2個(gè)臨床試驗(yàn)研究共1 451例ARDS患者，根據(jù)ARDS的病因?qū)⑵浞譃閯?chuàng)傷相關(guān)性ARDS(主要病因?yàn)閯?chuàng)傷)與非創(chuàng)傷相關(guān)性ARDS(主要病因?yàn)榉莿?chuàng)傷)兩組，結(jié)果顯示創(chuàng)傷相關(guān)性ARDS患者更加年輕、急慢性疾病更少，血漿中反映肺上皮細(xì)胞和內(nèi)皮細(xì)胞損傷的標(biāo)志物可溶性細(xì)胞黏附分子-1(sICAM-1)、vWF、SP-D、可溶性腫瘤壞死因子受體-1(TNFr-1)水平更低，90 d死亡率更低，與之前諸多研究結(jié)果相同[35-40]。該研究還顯示，創(chuàng)傷相關(guān)性ARDS患者的死亡率低，并不足以用其基礎(chǔ)臨床差異來(lái)解釋，可能由其肺上皮、內(nèi)皮細(xì)胞損傷較輕引起。近年來(lái)人們對(duì)創(chuàng)傷后發(fā)生ARDS的危險(xiǎn)因素進(jìn)行了深入研究，發(fā)現(xiàn)PPFIA1基因[41]、血清低水平的內(nèi)皮細(xì)胞特異分子-1[42]、主動(dòng)與被動(dòng)吸煙[43]等與創(chuàng)傷相關(guān)性ARDS發(fā)生有一定關(guān)系。

REILLY等[44]進(jìn)一步對(duì)創(chuàng)傷相關(guān)性ARDS進(jìn)行了潛類別分析，發(fā)現(xiàn)早發(fā)型ARDS(創(chuàng)傷后48 h內(nèi)發(fā)生)患者與晚發(fā)型ARDS(創(chuàng)傷后48 h后發(fā)生)患者相比，胸部創(chuàng)傷更嚴(yán)重、入住重癥監(jiān)護(hù)室(ICU)前最低收縮壓更低，且早發(fā)型ARDS患者血漿Ang-2、可溶性晚期糖基化終末產(chǎn)物受體(sRAGE)水平較晚發(fā)型高，提示早發(fā)型ARDS患者肺泡-毛細(xì)血管屏障的損傷可能更嚴(yán)重[45-46]，但兩類患者的院內(nèi)病死率并無(wú)差異。這種早發(fā)型ARDS患者更適于以糖基化終末產(chǎn)物受體(RAGE)和Ang-2為靶點(diǎn)的治療方案。RAGE是一種多配體受體，屬于細(xì)胞表面分子免疫球蛋白超家族，其能與多種配體(如晚期糖基化產(chǎn)物、淀粉樣肽、高遷移率族蛋白)結(jié)合，參與炎性反應(yīng)和固有免疫反應(yīng)。既往研究結(jié)果顯示，阻斷RAGE軸可以減輕炎性反應(yīng)程度，提高膿毒癥小鼠的生存率[47]。Ang-2是一種內(nèi)皮細(xì)胞生長(zhǎng)因子，主要表達(dá)于血管內(nèi)皮細(xì)胞，可識(shí)別Tie-2。靜息狀態(tài)下血管內(nèi)皮細(xì)胞的Ang-2表達(dá)量較少，當(dāng)內(nèi)皮細(xì)胞活化時(shí)其表達(dá)上調(diào)，拮抗Ang-1與Tie-2結(jié)合所致的穩(wěn)定內(nèi)皮細(xì)胞的作用，導(dǎo)致內(nèi)皮細(xì)胞凋亡和血管滲漏。研究表明，以核酸適體或封閉抗體抑制Ang-2，阻斷其與Tie-2結(jié)合，可發(fā)揮抗感染效應(yīng)、減輕血管滲漏[48]，這同樣為ARDS的臨床治療提供了新思路。

3 膿毒癥表型

2010年SHEU等[49]納入2 786例可能發(fā)展為ARDS的患者，其中736例最終發(fā)生了ARDS，將由膿毒癥引起的ARDS歸為膿毒癥相關(guān)性ARDS(524例)，將由非膿毒癥損傷(如創(chuàng)傷、誤吸、多次輸血)造成的ARDS歸為非膿毒癥相關(guān)性ARDS(62例)，將同時(shí)有膿毒癥及創(chuàng)傷、誤吸、多次輸血等危險(xiǎn)因素的患者排除在外。該研究發(fā)現(xiàn)，膿毒癥相關(guān)性ARDS患者的病情更加嚴(yán)重、肺損傷恢復(fù)更差、成功拔管率更低、60 d病死率更高。分析其原因，膿毒癥相關(guān)性ARDS患者的血漿降鈣素原(PCT)、vWF抗原、sICAM-1、可溶性E選擇素水平較非膿毒癥相關(guān)性ARDS患者更高，提示前者的急性炎性反應(yīng)、內(nèi)皮細(xì)胞活性、凝血激活程度更高。

循環(huán)內(nèi)皮細(xì)胞是內(nèi)皮細(xì)胞破壞的標(biāo)志物[50-51]。MOUSSA等[52]的研究結(jié)果顯示，中重度膿毒癥相關(guān)性ARDS患者循環(huán)內(nèi)皮細(xì)胞(CEC)計(jì)數(shù)高于輕度膿毒癥相關(guān)性ARDS患者，死亡患者的CEC計(jì)數(shù)高于存活者，提示內(nèi)皮細(xì)胞破壞在膿毒癥相關(guān)性ARDS的發(fā)病中可能起重要作用，可能是其嚴(yán)重程度的標(biāo)志物。A型血[53]、中性粒細(xì)胞相關(guān)基因的過(guò)表達(dá)[54]可能是膿毒癥相關(guān)性ARDS發(fā)生的危險(xiǎn)因素。既往研究結(jié)果表明，骨髓間充質(zhì)干細(xì)胞可發(fā)揮抗感染和抗凋亡效應(yīng)、調(diào)節(jié)上皮細(xì)胞和內(nèi)皮細(xì)胞通透性、改善肺水清除等，進(jìn)而減輕膿毒癥和ARDS中的肺損傷，增強(qiáng)肺修復(fù)[55]。

3-羥基-3-甲基戊二酸單酰輔酶A(HMG-CoA)還原酶抑制劑(他汀類)藥物除抗感染、免疫調(diào)節(jié)、抗氧化等作用外，還具有促進(jìn)內(nèi)皮細(xì)胞骨架重排、減輕氧化應(yīng)激等作用。動(dòng)物實(shí)驗(yàn)證實(shí)，他汀類藥物可減輕呼吸機(jī)相關(guān)性肺損傷和內(nèi)毒素所致的肺損傷中的血管滲漏[56-57]。雖然也有研究結(jié)果顯示，瑞舒伐他汀對(duì)膿毒癥相關(guān)性ARDS患者的60 d院內(nèi)生存率、機(jī)械通氣時(shí)間無(wú)明顯改善[58]。但MANSUR等[59]進(jìn)一步將膿毒癥相關(guān)性ARDS的嚴(yán)重程度進(jìn)行分級(jí)，發(fā)現(xiàn)在白種人中辛伐他汀預(yù)處理及連續(xù)治療可以改善重度膿毒癥相關(guān)性ARDS患者的28 d生存率，對(duì)預(yù)后有益。

4 炎癥表型

2014年CALFEE等[60]納入2個(gè)相互獨(dú)立的隨機(jī)對(duì)照試驗(yàn)(ARMA研究的473例和ALVEOLI研究的549例ARDS患者)，潛類別分析提示，將ARDS分為非超炎型、超炎型2個(gè)亞型為最優(yōu)擬合。超炎型ARDS為具有相對(duì)高血漿水平的IL-6、IL-8、TNFr-1、纖溶酶原激活物抑制因子-1(PAI-1)及相對(duì)較快的心率和較大1 min通氣量，相對(duì)低的收縮壓、碳酸氫根離子及C反應(yīng)蛋白水平的ARDS。非超炎型ARDS為具有相對(duì)低血漿水平的IL-6、IL-8、TNFr-1、PAI-1及相對(duì)較慢的心率和較小的1 min通氣量，相對(duì)高的收縮壓、碳酸氫根離子及C反應(yīng)蛋白水平的ARDS。超炎型患者與非超炎型相比其血漿炎性反應(yīng)標(biāo)志物水平更高、升壓藥使用更加普遍、血清碳酸氫鹽水平更低、膿毒血癥患病率更高。超炎型患者與非超炎型相比臨床結(jié)局更差，病死率更高、自主呼吸天數(shù)和無(wú)器官衰竭天數(shù)更少。

在ALVEOLI研究中，PEEP對(duì)兩種類型ARDS患者的90 d病死率、自主呼吸天數(shù)及無(wú)器官衰竭天數(shù)有不同的影響。該研究提示，超炎型ARDS型患者炎性反應(yīng)、休克、代謝性酸中毒更加嚴(yán)重，且臨床結(jié)局更差；兩種類型ARDS患者對(duì)PEEP的反應(yīng)也不同，超炎型患者運(yùn)用高PEEP與低PEEP相比可降低病死率，而非超炎型患者運(yùn)用高PEEP的病死率更高。一項(xiàng)納入了3個(gè)隨機(jī)對(duì)照試驗(yàn)的meta分析結(jié)果顯示，氧合指數(shù)≤200 mm Hg(1 mm Hg=0.133 kPa)的ARDS患者運(yùn)用較高PEEP與低PEEP相比可使病死率降低5%，而氧合指數(shù)>200 mm Hg的ARDS患者運(yùn)用高PEEP卻使病死率升高[61]。CALFEE等[60]的ARDS分型對(duì)PEEP反應(yīng)的差異較氧合指數(shù)對(duì)PEEP反應(yīng)的差異更加明顯，提示其分型可能比單純以氧合指數(shù)進(jìn)行分型對(duì)指導(dǎo)臨床治療的意義更大。同時(shí)，CALFEE等[60]的研究也存在一定不足，包括：其采用的是傳統(tǒng)的ARDS預(yù)后標(biāo)志物，如應(yīng)用基因或代謝標(biāo)志物可能有利于更全面的分型；研究無(wú)法將酗酒[62]、吸煙[43]、肥胖[63]等可能變量納入分析，這均有待后續(xù)研究的完善。

5 影像學(xué)表型

MROZEK等[64]根據(jù)胸部CT表現(xiàn)將119例ARDS患者分為局灶型和非局灶型。局灶型指胸部CT提示肺密度增加呈葉段分布，非局灶型指肺密度增加呈彌漫性分布。當(dāng)患者病情不允許行胸部CT檢查時(shí)，以胸部正位片或肺部超聲檢查代替，肺密度增加區(qū)域主要位于肺下葉時(shí)將患者納入局灶型組，當(dāng)肺密度增加區(qū)域在肺上葉及下葉均勻分布時(shí)將患者納入非局灶型組。最終局灶型組納入了32例(26.9%)ARDS患者，非局灶型組納入了87例(73.1%)ARDS患者。非局灶型組中位血漿sRAGE水平為3 074(1 930，4 404)μg/L，明顯高于局灶型組的877(494，1 049)μg/L。采用血漿sRAGE水平區(qū)分局灶型和非局灶型ARDS，受試者工作特征(ROC)曲線下面積為0.93，當(dāng)最佳截?cái)嘀禐? 188 μg/L時(shí)，靈敏度為93%，特異度為84%。多因素分析，結(jié)果顯示ARDS患者的血漿sRAGE水平對(duì)胸部CT表型、簡(jiǎn)化急性生理狀態(tài)評(píng)分系統(tǒng)(SAPS)Ⅱ評(píng)分、平臺(tái)壓有影響。非局灶型ARDS患者28 d及90 d病死率均高于局灶型組；對(duì)ARDS死亡危險(xiǎn)因素進(jìn)行多因素分析，結(jié)果顯示只有血漿sRAGE水平、SAPSⅡ評(píng)分是ARDS患者死亡的獨(dú)立危險(xiǎn)因素。血漿sRAGE水平作為ARDS中反映Ⅰ型肺泡上皮細(xì)胞損傷和肺泡液體清除率的標(biāo)志物[65-67]，該結(jié)果也提示非局灶型ARDS肺泡液體清除率受損較局灶型ARDS更嚴(yán)重，且血漿sRAGE水平可作為基于胸部CT表現(xiàn)的ARDS分型。CONSTANTIN等[68]的研究結(jié)果表明，肺復(fù)張策略可改善彌漫性肺通氣減低的ARDS患者的動(dòng)脈血氧分壓，卻無(wú)法改善局灶性通氣減低的ARDS患者的動(dòng)脈血氧分壓。由于局灶型ARDS和非局灶型ARDS的病死率及對(duì)機(jī)械通氣的反應(yīng)可能存在不同，對(duì)于局灶型和非局灶型ARDS患者機(jī)械通氣方案?jìng)€(gè)體化的研究也正在進(jìn)行中。

綜上所述，不同表型的ARDS在發(fā)病機(jī)制、臨床表現(xiàn)、治療方案、預(yù)后等諸多方面存在差異，但目前尚無(wú)一種完美的分型方法可以指導(dǎo)ARDS的臨床治療，仍需要大量的基礎(chǔ)及臨床研究。

作者貢獻(xiàn)：楊卿進(jìn)行文獻(xiàn)檢索并撰寫論文；顏春松進(jìn)行文章的構(gòu)思與設(shè)計(jì)、論文的中英文修訂，負(fù)責(zé)文章的質(zhì)量控制及審校，對(duì)文章整體負(fù)責(zé)，監(jiān)督管理。

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[1]ASHBAUGH D G,BIGELOW D B,PETTY T L,et al.Acute respiratory distress in adults[J].Lancet,1967,2(7511):319-323.DOI:10.1016/S0140-6736(67)90168-7.

[2]PETTY T L,ASHBAUGH D G.The adult respiratory distress syndrome:clinical features,factors influencing prognosis and principles of management[J].Chest,1971,60(3):233-239.DOI:10.1378/chest.60.3.233.

[3]PETTY T L.Indicators of risk,course,and prognosis in adult respiratory distress syndrome(ARDS)[J].Am Rev Respir Dis,1985,132(3):471.

[4]MURRAY J F,MATTHAY M A,LUCE J M,et al.An expanded definition of the adult respiratory distress syndrome[J].Am Rev Respir Dis,1988,138(3):720-723.DOI:10.1164/ajrccm/138.3.720.

[5]BERNARD G R,ARTIGAS A,BRIGHAM K L,et al.The American-European Consensus Conference on ARDS:definitions,mechanisms,relevant outcomes,and clinicaltrial coordination[J].Am J Respir Crit Care Med,1994,149(3 pt 1):818-824.DOI:http://dx.doi.org/10.1164/ajrccm.149.3.7509706.

[6]RAGHAVENDRAN K,NAPOLITANO L M.Definiton of ALI/ARDS[J].Crit Care Clin,2011,27(3):429-437.DOI:10.1016/j.ccc.2011.05.006.[7]SARMIENTO X,GUARDIOLA J J,ALMIRALL J,et al.Discrepancy between clinical criteria for diagnosing acute respiratory distress syndrome secondary to community acquired pneumonia with autopsy findings of diffuse alveolar damage[J].Respir Med,2011,15(8):1170-1175.DOI:10.1016/j.rmed.2011.04.001.[8]PINHEIRO B V,MURAOKA F S,ASSIS R V,et al.Accuracy of clinical diagnosis of acute respiratory distress syndrome in comparison with autopsy findings[J].J Bras Pneumol,2007,33(4):423-428.DOI:10.1590/S1806-37132007000400011.

[9]ARDS Definition Task Force,RANIERI V M,RUBENFELD G D,et al.Acute respiratory distress syndrome:the Berlin Definition[J].JAMA,2012,307(23):2526-2533.DOI:10.1001/jama.2012.5669.

[10]BELLANI G,LAFFEY J G,PHAM T,et al.Epidemiology,patterns of care,and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries[J].JAMA,2016,23,315(8):788-800.DOI:10.1001/jama.2016.0291.

[11]GATTINONI L,PELOSI P,SUTER P M,et al.Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease.Different syndromes?[J].Am J Respir Crit Care Med,1998,158(1):3-11.DOI:10.1001/jama.2012.5669.

[12]PERES E SERRA A,PARRA E R,EHER E,et al.Nonhomogeneous immunostaining of hyaline membranes in different manifestations of diffuse alveolar damage[J].Clinics(Sao Paulo),2006,61(6):497-502.DOI:10.1590/S1807-59322006000600002.

[13]HOELZ C,NEGRI E M,LICHTENFELS A J,et al.Morphometric differences in pulmonary lesions in primary and secondary ARDS.A preliminary study in autopsies[J].Pathol Res Pract,2001,197(8):521-530.DOI:10.1016/S0344-0338(04)70122-3.

[14]MENEZES S L,BOZZA P T,NETO H C,et al.Pulmonary and extrapulmonary acute lung injury:inflammatory and ultrastructural analyses[J].J Appl Physiol(1985),2005,98(5):1777-1783.DOI:10.1152/japplphysiol.01182.2004.

[15]SANTOS F B,NAGATO L K,BOECHEM N M,et al.Time course of lung parenchyma remodeling in pulmonary and extrapulmonary acute lung injury[J].J Appl Physiol(1985),2006,100(1):98-106.DOI:10.1152/japplphysiol.00395.2005.

[16]GOODMAN L R,FUMAGALLI R,TAGLIABUE P,et al.Adult respiratory distress syndrome due to pulmonary and extrapulmonary causes:CT,clinical,and functional correlations[J].Radiology,1999,213(2):545-552.DOI:10.1148/radiology.213.2.r99n v42545.

[17]DESAI S R,WELLS A U,SUNTHARALINGAM G,et al.Acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury:a comparative CT study[J].Radiology,2001,218(3):689-693.DOI:10.1148/radiology.218.3.r01mr31689.

[18]LIM C M,JUNG H,KOH Y,et al.Effect of alveolar recruitment maneuver in early acute respiratory distress syndrome according to antiderecruitment strategy,etiological category of diffuse lung injury,and body position of the patient[J].Crit Care Med,2003,31(2):411-418.DOI:10.1097/01.CCM.0000048631.88155.39.

[19]PELOSI P,BRAZZI L,GATTINONI L.Prone position in acute respiratory distress syndrome[J].Eur Respir J,2002,20(4):1017-1028.DOI:10.1183/09031936.02.00401702.

[20]徐軍，于學(xué)忠，馬遂，等.肺內(nèi)與肺外源性急性呼吸窘迫綜合征[J].國(guó)際呼吸雜志，2007，27(5)：329-332.DOI:10.3760/cma.j.issn.1673-436X.2007.05.004. XU J,YU X Z,MA S,et al.Pulmonary and extrapulmonary distress syndrome[J].Int J Respir,2007,27(5):329-332.DOI:10.3760/cma.j.issn.1673-436X.2007.05.004.

[21]ROUBY J J,PUYBASSET L,CLUZEL P,et al.Regional distribution of gas and tissue in acute respiratory distress syndrome.Ⅱ.Physiological correlations and definition of an ARDS severity score[J].Intensive Care Med,2000,26(8):1046-1056.DOI:10.1007/s001340051317.

[22]MONCHI M,BELLENFANT F,CARIOU A,et al.Early predictive factors of survival in the acute respiratory distress syndrome.A multivariate analysis[J].Am J Respir Crit Care Med,1998,158(4):1076-1081.DOI:10.1164/ajrccm.158.4.9802009.

[23]AGARWAL R,AGGARWAL A N,GUPTA D,et al.Etiology and outcomes of pulmonary and extrapulmonary acute lung injury/ARDS in a respiratory ICU in North India[J].Chest,2006,130(3):724-729.DOI:10.1378/chest.130.3.724.

[24]AGARWAL R,SRINIVAS R,NATH A,et al.Is the mortality higher in the pulmonary vs the extrapulmonary ARDS?A meta analysis[J].Chest,2008,133(6):1463-1473.DOI:10.1378/chest.07-2182.

[25]CALFEE C S,JANZ D R,BERNARD G R,et al.Distinct molecular phenotypes of direct versus indirect ARDS in single and multi-center studies[J].Chest,2015,147(6):1539-1548.DOI:10.1378/chest.14-2454.

[26]ALFIERI A,WATSON J J,KAMMERER R A,et al.Angiopoietin-1 variant reduces LPS-induced microvascular dysfunction in a murine model of sepsis[J].Crit Care,2012,16(5):R182.DOI:10.1186/cc11666.

[27]SUGIYAMA M G,ARMSTRONG S M,WANG C,et al.The Tie2-agonist Vasculotide rescues mice from influenza virus infection[J].Sci Rep,2015,5:11030.DOI:10.1038/SREP11030.

[28]MATHEW B,JACOBSON J R,BERDYSHEV E,et al.Role of sphingolipids in murine radiation-induced lung injury:protection by sphingosine 1-phosphate analogs[J].FASEB J,2011,25(10):3388-3400.DOI:10.1096/FJ.11-183970.[29]SZCZEPANIAK W S,ZHANG Y,HAGERTY S,et al.Sphingosine 1-phosphate rescues canine LPS-induced acute lung injury and alters systemic inflammatory cytokine production in vivo[J].Transl Res,2008,152(5):213-224.DOI:10.1016/j.trsl.2008.09.002.[30]PREUβ S,SCHEIERMANN J,STADELMANN S,et al.18∶1/18∶1-Dioleoyl-phosphatidylglycerol prevents alveolar epithelial apoptosis and profibrotic stimulus in a neonatal piglet model of acute respiratory distress syndrome[J].Pulm Pharmacol Ther,2014,28(1):25-34.

[31]WARE L B,MATTHAY M A.Keratinocyte and hepatocyte growth factors in the lung:roles in lung development,inflammation,and repair[J].Am J Physiol Lung Cell Mol Physiol,2002,282(5):L924-940.DOI:10.1152/ajplung.00439.2001.

[32]TEJERA P,MEYER N J,CHEN F,et al.Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin[J].J Med Genet,2012,49(11):671-680.DOI:10.1136/jmedgenet-2012-100972.

[33]GONG M N,ZHOU W,WILLIAMS P L,et al.-308GA and TNFB polymorphisms in acute respiratory distress syndrome[J].Eur Respir J,2005,26(3):382-389.DOI:10.1183/09031936.05.00000505.[34]CALFEE C S,EISNER M D,WARE L B,et al.Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders[J].Crit Care Med,2007,35(10):2243-2250.DOI:10.1097/01.CCM.0000280434.33451.87.[35]FLORI H R,WARE L B,GLIDDEN D,et al.Early elevation of plasma soluble intercellular adhesion molecule-1 in pediatric acute lung injury identifies patients at increased risk of death and prolonged mechanical ventilation[J].Pediatr Crit Care Med,2003,4(3):315-321.DOI:10.1097/01.PCC.0000074583.27727.8E.

[36]WARE L B,EISNER M D,THOMPSON B T,et al.Significance of von willebrand factor in septic and nonseptic patients with acute lung injury[J].Am J Respir Crit Care Med,2004,170(7):766-772.DOI:10.1164/rccm.200310-1434OC.

[37]PARSONS P E,MATTHAY M A,WARE L B,et al.Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury[J].Am J Physiol Lung Cell Mol Physiol,2005,288(3):L426-431.DOI:10.1152/ajplung.00302.2004.

[38]EISNER M D,PARSONS P,MATTHAY M A,et al.Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury[J].Thorax,2003,58(11):983-988.DOI:10.1136/thorax.58.11.983.

[39]STAPLETON R D,WANG B M,HUDSON L D,et al.Causes and timing of death in patients with ARDS[J].Chest,2005,128(2):525-532.DOI:10.1378/chest.128.2.525.

[40]RUBENFELD G D,CALDWELL E,PEABODY E,et al.Incidence and outcomes of acute lung injury[J].N Engl J Med,2005,354(4):1685-1693.DOI:10.1056/NEJMoa050333.

[41]CHRISTIE J D,WURFEL M M,FENG R,et al.Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma[J].PLoS One,2012,7(1):e28268.DOI:10.1371/journal.pone.0028268.

[42]MIKKELSEN M E,SHAH C V,SCHERPEREEL A,et al.Lower serum endocan levels are associated with the development of acute lung injury after major trauma[J].J Crit Care,2012,27(5):522.DOI:10.1016/j.jcrc.2011.07.077.

[43]CALFEE C S,MATTHAY M A,EISNER M D,et al.Active and passive cigarette smoking and acute lung injury after severe blunt trauma[J].Am J Respir Crit Care Med,2011,183(12):1660-1665.DOI:10.1164/rccm.201011-1802OC.

[44]REILLY J P,BELLAMY S,SHASHATY M G,et al.Heterogeneous phenotypes of acute respiratory distress syndrome after major trauma[J].Ann Am Thorac Soc,2014,1(5):728-736.DOI:10.1513/AnnalaATS.201308-2800C.

[45]UCHIDA T,SHIRASAWA M,WARE L B,et al.Receptor for advanced glycation end-products is a marker of type Ⅰ cell injury in acute lung injury[J].Am J Respir Crit Care Med,2006,173(9):1008-1015.DOI:10.1164/rccm.200509-1477OC.[46]TERPSTRA M L,AMAN J,VAN NIEUW AMERONGEN GP,et al.Plasma biomarkers for acute respiratory distress syndrome:a systematic review and meta-analysis[J].Crit Care Med,2014,42(3):691-700.DOI:10.1097/01.ccm.0000435669.60811.24.

[47]CREAGH-BROWN B C,QUINLAN G J,EVANS T W,et al.The RAGE axis in systemic inflammation,acute lung injury and myocardial dysfunction:an important therapeutic target?[J].Intensive Care Med,2010,36(10):1644-1656.DOI:10.1007/s00134-010-1952-z.

[48]VAN DER HEIJDEN M,VAN NIEUW AMERONGEN GP,CHEDAMNI S,et al.The angiopoietin-Tie2 system as a therapeutic target in sepsis and acute lung injury[J].Expert Opin Ther Targets,2009,13(1):39-53.DOI:10.1517/14728220 802626256.

[49]SHEU C C,GONG M N,ZHAI R,et al.Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS[J].Chest,2010,138(3):559-567.DOI:10.1378/chest.09-2933.

[50]BLANN A D,WOYWODT A,BERTOLINI F,et al.Circulating endothelial cells.Biomarker of vascular disease[J].Thromb Haemost,2005,93(2):228-235.DOI:10.1267/THRO05020 228.

[51]WOYWODT A,BLANN A D,KIRSCH T,et al.Isolation and enumeration of circulating endothelial cells by immunomagnetic isolation:proposal of a definition and a consensus protocol[J].J Thromb Haemost,2006,4(3):671-677.DOI:10.1111/j.1538-7836.2006.01794.

[52]MOUSSA M D,SANTONOCITO C,FAGNOUL D,et al.Evaluation of endothelial damage in sepsis-related ARDS using circulating endothelial cells[J].Intensive Care Med,2015,41(2):231-238.DOI:10.1007/s00134-014-3589-9.

[53]REILLY J P,MEYER N J,SHASHATY M G,et al.ABO blood type A is associated with increased risk of ARDS in whites following both major trauma and severe sepsis[J].Chest,2014,145(4):753-761.DOI:10.1378/chest.13-1962.

[54]KANGELARIS K N,PRAKASH A,LIU K D,et al.Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS[J].Am J Physiol Lung Cell Mol Physiol,2015,308(11):L1102-1113.DOI:10.1152/ajplung.00380.2014.

[55]WALTER J,WARE L B,MATTHAY M A.Mesenchymal stem cells:mechanisms of potential therapeutic benefit in ARDS and sepsis[J].Lancet Respir Med,2014,2(12):1016-1026.DOI:10.1016/S2213-2600(14)70217-6.

[56]JACOBSON J R,BARNARD J W,GRIGORYEV D N,et al.Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury[J].Am J Physiol Lung Cell Mol Physiol,2005,288(6):L1026-1032.DOI:10.1152/ajplung.00354.2004.

[57]MüLLER H C,HELLWIG K,ROSSEAU S,et al.Simvastatin attenuates ventilator-induced lung injury in mice[J].Crit Care,2010,14(4):R143.DOI:10.1186/cc9209.

[58]TRUWIT J D,BERNARD G R,STEINGRUB J,et al.Rosuvastatin for sepsis-associated acute respiratory distress syndrome[J].N Engl J Med,2014,370(23):2191-2200.DOI:10.1056/NEJMoa1401520.

[59]MANSUR A,STEINAU M,POPOV A F,et al.Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome(ARDS) depends on ARDS severity:a prospective observational cohort study[J].BMC Med,2015,13(1):128.DOI:10.1186/s12916-015-0368-6.

[60]CALFEE C S,DELUCCHI K,PARSONS P E,et al.Subphenotypes in acute respiratory distress syndrome:latent class analysis of data from two randomised controlled trials[J].Lancet Respir Med,2014,2(8):611-620.DOI:10.1016/S2213-2600(14)70097-9.

[61]BRIEL M,MEADE M,MERCAT A,et al.Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome:systematic review and meta-analysis[J].JAMA,2010,303(9):865-873.DOI:10.1001/jama.2010.218.

[62]MOSS M,BUCHER B,MOORE F A,et al.The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults[J].JAMA,1996,275(1):50-54.DOI:10.1001/jmam.275.1.50.

[63]STAPLETON R D,SURATT B T.Obesity and nutrition in acute respiratory distress syndrome[J].Clin Chest Med,2014,35(4):655-671.DOI:10.1016/j.ccm.2014.08.005.

[64]MROZEK S,JABAUDON M,ABER S,et al.Elevated plasma levels of sRAGE are associated with Non-focal CT-based lung imaging in ARDS patients:a prospective multicenter study[J].Chest,2016,150(5):998-1007.DOI:10.1016/j.chest.2016.03.016.

[65]JABAUDON M,FUTIER E,ROSZYK L,et al.Soluble form of the receptor for advanced glycation end products is a marker of acute lung injury but not of severe sepsis in critically ill patients[J].Critical Care Medicine,2011,39(3):480-488.DOI:10.1097/CCM.0b013e318206b3a.

[66]JABAUDON M,BLONDONNET R,ROSZYK L,et al.Soluble receptor for advanced glycation end-products predicts impaired alveolar fluid clearance in acute respiratory distress syndrome[J].Am J Respir Crit Care Med,2015,192(2):191-199.DOI:10.1164/rccm.201501-0020OC.

[67]DOWNS C A,KREINER L H,JOHNSON N M,et al.Receptor for advanced glycation end-products regulates lung fluid balance via protein kinase C-gp91(phox) signaling to epithelial sodium channels[J].Am J Respir Cell Mol Biol,2015,52(1):75-87.DOI:10.1165/rcmb.2014-0002OC.

[68]CONSTANTIN J M,CAYOT-CONSTANTIN S,ROSZYK L,et al.Response to recruitment maneuver influences net alveolar fluid clearance in acute respiratory distress syndrome[J].Anesthesiology,2007,106(5):944-951.DOI:10.1097/01.anes.0000265153.17062.64.

(本文編輯：王鳳微)

Research Progress on Heterogeneity of Acute Respiratory Distress Syndrome

YANGQing,YANChun-song*

RespiratoryMedicineDepartment,theSecondAffiliatedHospitalofNanchangUniversity,Nanchang330006,China

*Correspondingauthor:YANChun-song,Professor,Mastersupervisor;E-mail:ycs65@126.com

Acute respiratory distress syndrome(ARDS) is a heterogeneous syndrome that differs in different cases in terms of etiology,pathogenesis,clinical manifestations,treatment regimen,prognosis and other aspects.And based on these differences,we can classify ARDS into different phenotypes in order to guide clinical therapy and judge prognosis.This article reviewed the recent developments in heterogeneity and phenotypes of ARDS.

Respiratory distress syndrome,adult;Heterogeneity;Phenotype

R 563.8

A

10.3969/j.issn.1007-9572.2017.13.023

2016-11-03；

2017-01-24)

330006 江西省南昌市，南昌大學(xué)第二附屬醫(yī)院呼吸內(nèi)科

*通信作者：顏春松，教授，碩士生導(dǎo)師；

E-mail：ycs65@126.com