雄激素對機體嚴重創(chuàng)傷后免疫反應(yīng)、肝臟及心血管功能的影響

楊開超，耿 磊，朱曉光，封啟明

(上海交通大學(xué)附屬第六人民醫(yī)院急診科，上海 200233)

·綜 述·

雄激素對機體嚴重創(chuàng)傷后免疫反應(yīng)、肝臟及心血管功能的影響

楊開超，耿 磊，朱曉光，封啟明

(上海交通大學(xué)附屬第六人民醫(yī)院急診科，上海 200233)

動物研究證實，創(chuàng)傷預(yù)后存在明顯的性別差異，雄性動物創(chuàng)傷后并發(fā)癥發(fā)生率及死亡率均明顯高于雌性。但是，臨床關(guān)于創(chuàng)傷預(yù)后性別差異的研究則一直存在爭議。實驗室研究證實，雄性動物創(chuàng)傷后機體免疫反應(yīng)及各臟器功能明顯受到抑制，而睪丸切除或服用雄激素受體抑制劑后上述抑制作用得到明顯改善。關(guān)于性激素水平對創(chuàng)傷后機體免疫反應(yīng)的研究發(fā)現(xiàn)，雌激素具有免疫增強作用；而相反，雄激素則會誘導(dǎo)免疫抑制。本文主要闡述雄激素水平變化對機體創(chuàng)傷后免疫反應(yīng)、肝臟及心血管系統(tǒng)功能的影響作用，進一步分析創(chuàng)傷預(yù)后性別差異的潛在機制，從而在動物研究的結(jié)果中尋求新的干預(yù)措施來改善創(chuàng)傷患者的預(yù)后。

創(chuàng)傷；雄激素；免疫反應(yīng)；肝臟；心血管

動物研究證實，創(chuàng)傷預(yù)后存在明顯的性別差異。而臨床研究對此卻一直存在爭議，部分研究表明女性創(chuàng)傷患者創(chuàng)傷后死亡率或嚴重并發(fā)癥發(fā)生率明顯低于男性[1-7]，而還有一部分研究則認為女性患者預(yù)后與男性相比無明顯差異[8-9]。研究還發(fā)現(xiàn)創(chuàng)傷患者預(yù)后性別差異具有年齡特異性。Wohltmann等[3]對約2萬創(chuàng)傷患者分析發(fā)現(xiàn)，年齡＜50歲的女性嚴重創(chuàng)傷患者亡率明顯低于同齡男性，而年齡≥50歲的女性患者與同齡男性相比無明顯差異。Frink等[10]研究也發(fā)現(xiàn)年齡＜50女性嚴重創(chuàng)傷患者MOF及膿毒癥的發(fā)生率均明顯低于同齡男性患者。動物研究表現(xiàn)為雄性動物創(chuàng)傷后機體免疫反應(yīng)及各臟器功能均受到抑制，而發(fā)情期雌性動物創(chuàng)傷后則表現(xiàn)為免疫增強，各臟器功能維持在正常水平[11-12]。機體創(chuàng)傷失血后免疫反應(yīng)及各臟器功能依賴于性激素水平的變化，不同類型或不同水平的性激素均有可能導(dǎo)致創(chuàng)傷后機體免疫反應(yīng)及各臟器功能變化的性別差異。女性在50歲左右經(jīng)歷絕經(jīng)期，絕經(jīng)后女性體內(nèi)雌激素水平下降，而雄激素水平則無明顯變化。而還有研究發(fā)現(xiàn)，男性雄激素水平會隨著年齡的增長而逐漸下降[13]。動物研究證實雌激素具有免疫保護作用，而雄激素則誘導(dǎo)免疫抑制。本文主要闡述在動物研究中雄激素水平對創(chuàng)傷后機體免疫反應(yīng)、肝臟及心血管系統(tǒng)的影響作用，進一步探討創(chuàng)傷預(yù)后性別差異的潛在機制。

1 雄激素水平的動態(tài)變化

雄激素主要以睪酮為主，研究發(fā)現(xiàn)睪酮水平會隨著年齡的增加逐漸下降。男性在30歲左右睪酮水平達到高峰，之后平均每年下降約1%，約有20%的男性在60歲以后，50%的男性在80歲以后血漿睪酮水平低于年輕男性血漿睪酮的正常下限[13-14]。循環(huán)系統(tǒng)中的睪酮大約有98%都綁定在血漿蛋白上，而性激素結(jié)合球蛋白(SHBG)正是血漿及白蛋白中睪酮的主要結(jié)合蛋白，只有1%～2%的睪酮處于游離狀態(tài)。因為睪酮與SHBG之間具有高親和力，所以與SHBG結(jié)合的睪酮無法為組織所利用。然而，睪酮與白蛋白的親和力較低，與白蛋白結(jié)合及循環(huán)中游離的睪酮對各組織來說才具有生物活性。研究發(fā)現(xiàn)血漿中SHBG的濃度會隨著年齡的增長而上升，所以結(jié)合性睪酮的比例也就會隨之增加，相反，具有生物活性的睪酮水平就會隨之下降。因此，有很大一部分老年人血漿中具有生物活性的睪酮水平要明顯低于年輕男性的正常水平的下限[13-15]。

2 雄激素對機體創(chuàng)傷后免疫、肝臟及心血管功能的影響

2.1 雄激素對免疫反應(yīng)的影響 創(chuàng)傷后機體過度的炎癥反應(yīng)(SIRS)及免疫抑制在膿毒癥及MODS的發(fā)生過程中起重要作用[16]。與雌二醇相反，睪酮對創(chuàng)傷后機體免疫功能產(chǎn)生抑制作用，而雄鼠睪丸切除后機體睪酮水平明顯下降，機體免疫功能則得到明顯改善。巨噬細胞在調(diào)節(jié)創(chuàng)傷后機體的免疫反應(yīng)中起重要作用。研究發(fā)現(xiàn)雄鼠創(chuàng)傷后脾細胞增殖能力明顯下降，脾細胞IL-2、3釋放能力明顯下降，脾臟及腹膜巨噬細胞IL-1、6釋放能力下降；而睪丸切除雄鼠創(chuàng)傷后脾細胞、脾臟及腹膜巨噬細胞上述炎癥因子釋放水平均明顯上升，同時脾細胞增殖能力也得到明顯改善[17-18]。Samy等[19]稱創(chuàng)傷失血能夠降低T淋巴細胞IL-6的釋放水平，而預(yù)先服用雄激素受體抑制劑(氟他米特)能夠明顯改善T淋巴細胞IL-6的釋放水平。Angele等[20]研究發(fā)現(xiàn)睪丸切除雄鼠創(chuàng)傷失血前后脾臟及腹膜巨噬細胞促炎因子IL-1β、IL-6及抗炎因子IL-10釋放水平無明顯變化，而預(yù)先給予DHT的睪丸切除雄鼠創(chuàng)傷失血后脾臟及腹膜巨噬細胞IL-1β、IL-6釋放水平明顯下降，IL-10釋放水平則明顯上升。Angele等[21]另一項研究發(fā)現(xiàn)睪丸切除雄鼠創(chuàng)傷失血前后脾細胞TH1細胞因子(IL-2、3，INF-γ)及TH2細胞因子(IL-10)釋放水平均無明顯變化，預(yù)先給予DHT后，IL-2、3，INF-γ的釋放水平明顯下降，而IL-10釋放水平則明顯增加。Mayr等[22]研究還發(fā)現(xiàn)雄鼠創(chuàng)傷后免疫抑制可能與其脾臟及腹膜巨噬細胞MHC-Ⅱ(Ia)表達抑制有關(guān)。Angele等[23]研究還發(fā)現(xiàn)雄鼠創(chuàng)傷后免疫抑制可能與細胞p38磷酸化有關(guān)，雄鼠創(chuàng)傷后脾臟及腹膜巨噬細胞p38磷酸化增加，預(yù)先睪丸切除后則可以抑制雌鼠p38蛋白磷酸化增加，而給予雙氫睪酮(DHT)的睪丸切除雄鼠p38蛋白磷酸化則再次增加。4-羥基-雄烯二酮(4-OHA)為5α-還原酶抑制劑，而后者介導(dǎo)睪酮向DHT的轉(zhuǎn)化。雄鼠創(chuàng)傷后T淋巴細胞5α-還原酶表達及其活性增加，進而睪酮向雙清睪酮轉(zhuǎn)化增加，從而誘導(dǎo)免疫抑制作用的產(chǎn)生[24]。Schneider等[25]研究也發(fā)現(xiàn)雄鼠創(chuàng)傷后血漿TNF-α、IL-6及IL-10水平上升，脾臟巨噬細胞TNF-α及IL-6釋放水平明顯下降，IL-10的釋放水平升高；而給予4-OHA后血漿TNF-α、IL-6及IL-10水平明顯下降，且巨噬細胞TNF-α、IL-6及IL-10釋放水平均趨于正?；?。

2.2 雄激素肝臟功能的影響 創(chuàng)傷會導(dǎo)致肝臟功能損傷，表現(xiàn)為肝臟α-谷胱甘肽s-轉(zhuǎn)移酶水平、髓過氧化酶活性、硝基酪氨酸形成明顯增加，而睪丸切除能夠明顯改善上述指標(biāo)[26-27]。IL-6是一種多效性細胞因子，創(chuàng)傷后IL-6具有免疫抑制介質(zhì)作用，研究發(fā)現(xiàn)創(chuàng)傷后血漿IL-6及肝臟IL-6 mRNA表達水平也明顯增加[26]。IL-6水平升高與宿主免疫功能改變及感染并發(fā)癥相關(guān)。枯否細胞是IL-6的主要來源，創(chuàng)傷后肝臟枯否細胞IL-6釋放水平增加[18]，而睪丸切除后雄鼠創(chuàng)傷后枯否細胞IL-6釋放水平則明顯下降，給予DHT后IL-6釋放水平則再次增加[20]，這可能是雄激素導(dǎo)致機體免疫抑制的一個潛在機制。ICAM-1是細胞粘附分子中免疫球蛋白超家族的一員，其在活化的血管內(nèi)皮細胞中表達，對調(diào)節(jié)白細胞跨血管內(nèi)皮細胞運動和炎癥反應(yīng)起重要作用。趨化因子，如細胞誘導(dǎo)中性粒細胞趨化因子(CINC)-1及CINC-3對中性粒細胞具有很強的趨化作用，可誘導(dǎo)中性粒細胞積聚，創(chuàng)傷后趨化因子產(chǎn)生過多會導(dǎo)致肝臟損傷，而中性粒細胞積聚減少能夠改善創(chuàng)傷后各器官的損傷程度[28]。Shimizu等[26]研究發(fā)現(xiàn)，創(chuàng)傷會導(dǎo)致肝臟NF-κB的DNA結(jié)合活性，細胞間粘附分子-1蛋白表達及中性粒細胞趨化因子(CINC-1和CINC-3)水平明顯增加；而該研究還發(fā)現(xiàn)，氟他米特能夠通過雌激素受體途徑降低NF-κB DNA的結(jié)合活性，抑制肝臟NF-κB活化，下調(diào)肝臟CINC-1、CINC-3及ICAM-1的表達水平，減少中性粒細胞積，從而改善肝臟損傷程度。大量證據(jù)表明，血紅素氧合酶(HO)-1可以降低各種細胞因子、粘附分子及趨化因子的表達，抑制中性粒細胞積聚，改善休克導(dǎo)致的器官損傷，而且氟他米特恰恰能夠增強HO-1表達[28]。此外，氟他米特還可以通過減少肝臟炎癥反應(yīng)、氧化應(yīng)激及細胞凋亡作用，從而改善肝臟的損傷程度。Kan等[27]研究發(fā)現(xiàn)創(chuàng)傷后雄鼠血漿及肝臟(組織、肝細胞及枯否細胞)TNF-α、IL-6、角質(zhì)細胞源性趨化因子及單核細胞趨化蛋白-1表達水平明顯升高，而氟他米特可以降低上述因子的表達水平；該研究還發(fā)現(xiàn)創(chuàng)傷后肝臟誘導(dǎo)型一氧化氮合酶表達增加，且肝細胞及肝臟枯否細胞DNA斷裂也增加，而氟他米特同樣可以改善上述情況。Schneider等[25]研究發(fā)現(xiàn)創(chuàng)傷后雄鼠枯否細胞噬細胞TNF-α、IL-6及IL-10釋放水平上升，而4-OHA能夠降低上述因子的表達水平。

2.3 雄激素對心血管功能的影響 創(chuàng)傷后心輸出量、心搏量及心肌收縮力明顯下降，總外周阻力升高；而睪丸切除雄鼠心輸出量、心搏量及心肌收縮力較前上升，總外周阻力則較前下降[29-33]。雄激素受體拮抗劑氟他米特同樣也能夠增加心輸出量、心搏量及心肌收縮力，降低總外周阻力[31，33-34]。此外，研究發(fā)現(xiàn)創(chuàng)傷后心肌細胞IL-6水平與心功能呈負相關(guān)[30，34]。Yang等[29]研究發(fā)現(xiàn)創(chuàng)傷后心臟IL-6蛋白水平、心肌細胞內(nèi)IL-6水平及心肌細胞IL-6 mRNA表達明顯升高，而睪丸切除雄鼠創(chuàng)傷后心臟IL-6蛋白水平及心肌細胞內(nèi)IL-6水平上升水平明顯降低，但心肌細胞IL-6 mRNA表達水平仍明顯增加。此外，研究還發(fā)現(xiàn)雄鼠創(chuàng)傷后心肌細胞ER-α and ER-β mRNA及蛋白表達下降，有意思的是，氟他米特能夠增加ER-α and ER-βmRNA及蛋白表達[32-33]。Hsieh等[31]研究發(fā)現(xiàn)創(chuàng)傷后心臟過氧化物酶體增生物激活受體γ共激活因子1(PGC-1)蛋白表達水平明顯下降，氟他米特能夠增加PGC-1的蛋白表達，而雌激素受體拮抗劑(ICI)則能夠阻斷氟他米特上述作用。該研究還發(fā)現(xiàn)創(chuàng)傷后心肌細胞線粒體中ATP含量明顯下降，而預(yù)先給予氟他米特后雄鼠心肌細胞線粒體中ATP含量明顯改善。

綜上所述，雄激素能夠抑制機體創(chuàng)傷后的免疫反應(yīng)，損傷肝臟及心血管功能，而睪丸切除或服用雄激素受體拮抗劑氟他米特能夠明顯改善上述有害作用，且該作用部分依賴雌激素受體途徑實現(xiàn)。此外，雄激素水平會隨著年齡的增加而逐漸下降。因此，雄激素水平的動態(tài)變化及其對創(chuàng)傷后機體各系統(tǒng)功能的有害作用可能是導(dǎo)致預(yù)后性別差異的重要影響因素。氟他米特作為一種新的治療措施，可能有利于改善創(chuàng)傷患者的預(yù)后。

3 局限性及未來研究方向

臨床對于創(chuàng)傷患者預(yù)后性別差異的研究結(jié)果還存在爭議，預(yù)后性別差異的機制也不清楚。目前關(guān)于性激素水平與創(chuàng)傷預(yù)后的研究主要集中于動物實驗，性激素水平與創(chuàng)傷患者預(yù)后的相關(guān)性及其對患者預(yù)后的影響作用我們還不清楚，女性患者絕經(jīng)后雌激素水平的下降或男性患者雄激素水平隨著年齡增長而逐漸地下降均有可能影響患者的預(yù)后；一種或多種性激素以及其他因素如X染色體相關(guān)基因多態(tài)性，均有可能是創(chuàng)傷患者預(yù)后性別差異的影響因素。我們需要進行更多的臨床研究來證實創(chuàng)傷患者預(yù)后性別差異的存在。同時，我們還需要進一步分析創(chuàng)傷時患者血漿性激素水平、后期性激素水平的動態(tài)變化及其峰值與預(yù)后的關(guān)系，探索性激素影響創(chuàng)傷患者預(yù)后的具體機制，從而尋找新穎的有效的干預(yù)措施來減少創(chuàng)傷后各種嚴重并發(fā)癥的發(fā)生率，降低死亡率。

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Effect of androgen on immune response,hepatic and cardiovascular functions after severely traumatic injury

YANG Kai-chao,GENG Lei,ZHU Xiao-guang,FENG Qi-ming
Department of Emergency Medicine,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,Shanghai 200233,CHINA

It was well known that sexual difference exists in prognosis of trauma.Studies had revealed that there was a significantly higher incidence of life-threatening complications and mortality in traumatized males than in females.However,clinical studies had showed controversial results on the role of gender in outcomes of severe traumatic patients.Laboratory studies of trauma had confirmed that immune response was markedly depressed in males but was normalized in castrated males.Moreover,administration of testosterone receptor antagonist following trauma-hemorrhage could also improve immune,hepatic and cardiovascular functions.Several studies were conducted to explore the effect of sex hormones on immune response and organ functions following trauma.These results had showed that estrogen played an important role in mediating immunoprotective effects.In contrast,androgen was immunosuppressive.In this review,we discussed the effect of androgen on immune response,hepatic and cardiovascular functions in an experimental model of trauma-hemorrhage,and further analyzed the potential mechanism which responsible for gender dimorphism in outcomes of trauma patients.The results gained from the experimental studies would be helpful in designing innovative therapeutic approaches for the treatment of trauma patients.

Trauma;Androgen;Immune response;Hepatic;Cardiovascular

R641

A

1003—6350(2014)15—2249—04

10.3969/j.issn.1003-6350.2014.15.0874

2014-02-12)

上海市科學(xué)技術(shù)委員會科研計劃項目(編號：12410710700)

封啟明。E-mail：fengqiming04@126.com