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有效針對(duì)新冠肺炎的“炎癥風(fēng)暴”——Omega-3多不飽和脂肪酸(亞麻籽油中含有不飽和脂肪酸高達(dá)50%以上)

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      新冠肺炎“炎癥風(fēng)暴”是近期公眾關(guān)注的諸多熱點(diǎn)話題之一;所謂“炎癥風(fēng)暴”即全身炎癥反應(yīng)綜合征(SIRS),人體的炎癥因子,不僅可以殺掉病毒,也會(huì)給自身造成損害,某些新冠患者后期可能突然啟動(dòng)了一個(gè)“炎癥風(fēng)暴”,結(jié)果導(dǎo)致各個(gè)器官的功能衰竭。那么應(yīng)該如何應(yīng)對(duì)“炎癥風(fēng)暴”呢?中南大學(xué)湘雅醫(yī)學(xué)院林韶輝博士撰文“有效針對(duì)新冠肺炎的“炎癥風(fēng)暴”——Omega-3多不飽和脂肪酸”,表達(dá)了自己的一些觀點(diǎn),或許會(huì)給大家一些思考和啟發(fā)。


一、新冠肺炎專家說(shuō)

1. 武漢金銀潭醫(yī)院:上海中山醫(yī)院重癥醫(yī)學(xué)科副主任鐘鳴醫(yī)生(2020年1月24到達(dá)武漢),2020年2月3日,南方人物周刊對(duì)鐘醫(yī)生進(jìn)行獨(dú)家專訪,提到救治初期,所面臨的困難之中,有的新冠患者后期可能突然啟動(dòng)了一個(gè)“炎癥風(fēng)暴”,這種炎癥風(fēng)暴導(dǎo)致了各個(gè)器官的功能衰竭,一旦進(jìn)入這個(gè)狀態(tài),我們的治療很難把它拉回來(lái)。


2. 武漢大學(xué)中南醫(yī)院:《美國(guó)醫(yī)學(xué)會(huì)雜志》2月7日在線發(fā)布了武漢大學(xué)中南醫(yī)院重癥監(jiān)護(hù)室(ICU)主任彭志勇博士領(lǐng)銜的一項(xiàng)回顧性分析,研究團(tuán)隊(duì)認(rèn)為,新冠肺炎致死的三大主要機(jī)制:


中性粒細(xì)胞增多,與細(xì)胞因子風(fēng)暴有關(guān);

D-二聚體升高反映凝血激活,提示持續(xù)的炎癥反應(yīng);

血尿素升高提示急性腎損傷,這是感染、休克和缺氧的綜合結(jié)果。


3. 種種跡象表明,這些重癥患者中發(fā)生了不可逆轉(zhuǎn)的“炎癥風(fēng)暴”。而一旦患者發(fā)生“炎癥風(fēng)暴”,糖皮質(zhì)激素是對(duì)抗炎癥風(fēng)暴的武器之一,可以給免疫系統(tǒng)“滅火”,減輕機(jī)體損傷。不過(guò),糖皮質(zhì)激素是一把“雙刃劍”。一方面它可以減輕炎癥反應(yīng),有利于改善缺氧、呼吸窘迫癥狀;但長(zhǎng)期大劑量使用也可能引發(fā)諸多不良反應(yīng)。不少經(jīng)過(guò)大劑量激素治療的“非典”患者,都留下了如股骨頭壞死等嚴(yán)重后遺癥。


二、“炎癥風(fēng)暴”與Omega-3多不飽和脂肪酸

1. 炎癥反應(yīng)的發(fā)生:免疫應(yīng)激保護(hù)
過(guò)度炎癥反應(yīng)是ICU患者常見并發(fā)癥的主要誘因。促炎反應(yīng)與抗炎反應(yīng)的平衡狀態(tài),對(duì)機(jī)體全身性免疫反應(yīng)發(fā)生與否發(fā)揮重大作[1]應(yīng)激狀態(tài)下,炎性細(xì)胞如巨噬細(xì)胞、單核細(xì)胞、成纖維細(xì)胞和內(nèi)皮細(xì)胞活化,釋放促炎性細(xì)胞因子、血栓素A2、白三烯、血小板活化因子及氧自由基等炎癥介質(zhì)[2]。炎性細(xì)胞因子和炎性介質(zhì)一方面殺傷局部細(xì)胞和組織,另一方面刺激組織修復(fù)愈合。炎癥反應(yīng)是一把“雙刃劍”,需要抗炎介質(zhì)與促炎介質(zhì)在不同的環(huán)節(jié)上相互作用、相互拮抗,形成復(fù)雜的炎癥調(diào)控網(wǎng)絡(luò)[3]。
2. 炎癥反應(yīng)的失控:過(guò)度炎癥反應(yīng)(抗炎-促炎代謝失衡)會(huì)導(dǎo)致全身性炎癥反應(yīng)綜合征
如果抗炎性介質(zhì)分泌和釋放不足,炎癥反應(yīng)誘因持續(xù)強(qiáng)化,超出身體的代償能力,導(dǎo)致促炎性反應(yīng)調(diào)節(jié)失控,促炎-抗炎平衡失[4],促炎介質(zhì)占主導(dǎo)地[5],從而出現(xiàn)過(guò)度炎癥反應(yīng)。大量促炎介質(zhì)突破了局部的自限制作用,滲入血漿分布到身體其它部位。重要臟器的上皮細(xì)胞和血管內(nèi)皮細(xì)胞,可識(shí)別受損組織的炎癥信號(hào), 啟動(dòng)內(nèi)源性報(bào)警信號(hào)相關(guān)的免疫反應(yīng), 進(jìn)而引發(fā)全身性炎癥反應(yīng),最終導(dǎo)致全身多個(gè)器官出現(xiàn)功能性障礙,如急性肺損傷、多器官功能障礙綜合癥,甚至功能衰[6-8]

3. Omega-3 PUFA對(duì)抗炎癥反應(yīng)的作用機(jī)制

3.1 炎癥與脂肪酸代謝的關(guān)系
脂肪酸的代謝衍生物參與細(xì)胞代謝調(diào)控,和炎癥過(guò)程密不可分,圖1顯示的是不同脂肪酸的代謝途徑。
花生四烯酸(AA)是一種Omega 6 PUFA,代謝產(chǎn)生花生酸類(eicosanoids),花生四烯酸類脂質(zhì)經(jīng)一系列酶催化,產(chǎn)生促炎癥調(diào)節(jié)作用的前列腺素(PGE2)和白三烯B4等。這些促炎性介質(zhì)進(jìn)而可激活中性粒細(xì)胞、巨噬細(xì)胞,刺激炎癥細(xì)胞因子TNF-α、IL-1、IL-2、IL-8、干擾素(Interferon, IFN )等釋放增多。
另一類 PUFA同樣經(jīng)酶催化產(chǎn)生如消散素(resolvins)和保護(hù)素(protectins),刺激中性粒細(xì)胞和巨噬細(xì)胞等分泌產(chǎn)生抗炎性細(xì)胞因子IL-4、IL-10、IL-13等,來(lái)減弱炎癥反應(yīng),調(diào)節(jié)機(jī)體炎癥水[9, 10]


圖1. 長(zhǎng)鏈不飽和脂肪酸代謝示意圖



4. 多種文獻(xiàn)證明,為了減少患者還可能發(fā)生爆發(fā)性炎癥反應(yīng),使用高純度的  Omega-3 PUFA制劑,可以減低炎癥風(fēng)暴的發(fā)生風(fēng)險(xiǎn)。具體表現(xiàn)

4.1 Omega-3 PUFA富集于細(xì)胞膜,參與炎癥反應(yīng)調(diào)控過(guò)程,減少炎性細(xì)胞產(chǎn)生促炎性細(xì)胞因子;

Omega-3 PUFA富集于細(xì)胞膜,提高細(xì)胞膜EPA和DHA脂肪酸的比[11, 12],影響胞內(nèi)信號(hào)傳導(dǎo),抑制炎癥相關(guān)的轉(zhuǎn)錄因子NF-kappa B的轉(zhuǎn)錄活[13, 14],從而減少促炎性細(xì)胞因子TNF-alpha、IL-6 和IL-8等的表達(dá)[15]。

4.2 Omega-3 PUFA競(jìng)爭(zhēng)性抑制花生四烯酸代謝產(chǎn)生的促炎性介質(zhì);

花生四烯酸類脂質(zhì)經(jīng)一系列酶催化產(chǎn)生促炎癥調(diào)節(jié)作用的前列腺素(PGE2)和白三烯B4等。這些促炎性介質(zhì)進(jìn)而可激活中性粒細(xì)胞、巨噬細(xì)胞,刺激炎癥細(xì)胞因子TNF-α、IL-1、IL-2、IL-8和干擾素(Interferon, IFN)等釋放增多。Omega-3和Omega-6兩類 PUFA競(jìng)爭(zhēng)相同的脂肪酸代謝酶(Elovl5和FADS2)系統(tǒng)[16-18],從而干擾促炎性介質(zhì)的生成。

4.3 Omega-3 PUFA代謝生成具有消炎、止痛等生理活性的衍生物;

EPA和DHA經(jīng)代謝產(chǎn)生消散素(Resolvins)和保護(hù)素(Protections)。實(shí)驗(yàn)研究證實(shí),消散素和保護(hù)素在關(guān)節(jié)[19]、結(jié)腸[20]、哮[21, 22]等多種炎性疾病中發(fā)揮重要的抗炎作[23, 24] 。例如,resolvin E1,resolvin D1和protectin D1能抑制浸潤(rùn)性中性粒細(xì)胞的細(xì)胞遷移,從而減輕局部炎[24]。此外,resolvin D1和protectin D1還能抑制TNF-α and IL-1β的產(chǎn)生,從而減弱炎癥反應(yīng)[25, 26]

因此,Omega-3 PUFA能在各個(gè)層面調(diào)節(jié)炎癥反應(yīng),緩解全身性炎癥反應(yīng)綜合征的發(fā)生,從而為重癥疾患病人帶來(lái)臨床獲益。

5. Omega-3 PUFA緩解炎癥的具體臨床獲益

5.1 C反應(yīng)蛋白等炎癥指標(biāo)顯著下降,血紅蛋白和白細(xì)胞、血小板等細(xì)胞類群總量顯著上升。

德國(guó)漢諾威醫(yī)院一項(xiàng)面向重癥創(chuàng)傷病人的前瞻性、隨機(jī)、雙盲、對(duì)照試驗(yàn)[27] 證實(shí),ICU監(jiān)護(hù)期間開始使用含大約4克Omega-3 PUFA的營(yíng)養(yǎng)液,可以顯著降低患者的CRP水平。另一項(xiàng)針對(duì)膿血癥兒童的前瞻性,隨機(jī),雙盲,對(duì)照試驗(yàn)[28]發(fā)現(xiàn),補(bǔ)充Omega-3 PUFA顯著降低患者CRP、ESR、IL-6和白蛋白等炎性指標(biāo)的含量,還能明顯增加血紅蛋白含量和白細(xì)胞、血小板等細(xì)胞類群的細(xì)胞數(shù)量,從而縮短患者的ICU監(jiān)護(hù)時(shí)間。


表1. ICU患者使用Omega-3 PUFA帶來(lái)的生理指標(biāo)和臨床指標(biāo)獲益



5.2 敗血癥狀明顯下降,治療用抗生素使用時(shí)間縮短,全身炎癥反應(yīng)綜合征減少,器官功能障礙后遺癥發(fā)生率減少,死亡率下降;

美國(guó)田納西大學(xué)附屬醫(yī)院和西班牙多所醫(yī)院的臨床研究表明,對(duì)于重癥創(chuàng)傷患者和膿毒癥患者等ICU患者,每天1~3克Omega-3 PUFA營(yíng)養(yǎng)液可以有效降低菌血癥、敗血癥并發(fā)癥發(fā)生(下降14%[29]~35%[30]),明顯降低治療用抗生素使用時(shí)間和腹腔內(nèi)膿腫發(fā)生率[30]。而使用更高Omega-3 PUFA含量(4克以上)的營(yíng)養(yǎng)液后,創(chuàng)傷病人全身炎癥反應(yīng)綜合征發(fā)生人數(shù)顯著下[27];膿毒癥、敗血癥患者的器官功能障礙發(fā)生率減少達(dá)到43%[31],死亡率顯著下降13.1%[29]~19.4%[31]。



表2. 創(chuàng)傷患者和敗血癥患者使用Omega-3 PUFA的臨床獲益



5.3 改善氧合狀態(tài),減少呼吸機(jī)使用,縮短ICU監(jiān)護(hù)時(shí)間;

如表3所示,不同疾患類型的ICU患者補(bǔ)充Omega-3 PUFA,均能起到盡早脫離機(jī)械呼吸,縮短ICU監(jiān)護(hù)時(shí)間的臨床效果。


表3. 不同疾患類型的ICU患者補(bǔ)充Omega-3 PUFA對(duì)呼吸機(jī)使用時(shí)間和ICU監(jiān)護(hù)時(shí)間的影響


6. 推薦急性炎癥患者使用Omega-3 PUFA的特點(diǎn)
6.1 補(bǔ)充劑量和時(shí)間充分,保證對(duì)抗炎癥的。

6.2 生物利用度高,保證體內(nèi)有效富集。

6.3 添加中鏈甘油三酯(MCTs),促進(jìn)Omega-3 PUFA快速細(xì)胞富集,為重癥患者的癥狀緩解贏得時(shí)間。添加MCT的Omega-3脂肪乳的體內(nèi)富集時(shí)間更短(術(shù)后第六天即檢測(cè)到病患血清磷脂和紅細(xì)胞細(xì)胞膜中的EPA和DHA顯著升高[35],激發(fā)免疫更強(qiáng)(第六天起外周血細(xì)胞釋放的白三烯B5含量已增長(zhǎng)約2倍)[36]; 

三、總結(jié)
炎癥反應(yīng)的發(fā)展和體內(nèi)脂肪酸代謝的關(guān)系密不可分。Omega-3 PUFA富集于細(xì)胞膜,參與炎癥反應(yīng)調(diào)控過(guò)程,減少炎性細(xì)胞產(chǎn)生促炎性細(xì)胞因子,競(jìng)爭(zhēng)性降低炎性介質(zhì)的生成,調(diào)節(jié)免疫反應(yīng)[34, 37],從而緩解過(guò)度炎癥反應(yīng)[38],有效縮減患者的ICU監(jiān)護(hù)時(shí)間,減少全身性炎癥反應(yīng)患者的感染率和死亡[29, 39-41]。歐洲腸外腸內(nèi)營(yíng)養(yǎng)學(xué)會(huì)和美國(guó)腸內(nèi)腸外營(yíng)養(yǎng)學(xué)會(huì)一致推薦,手術(shù)患者、危重患者應(yīng)及早補(bǔ)充Omega-3 PUFA腸內(nèi)營(yíng)養(yǎng)液。

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