雌激素及雌激素受体信号转导途径在严重创伤中的作用及机制
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摘要
随着社会的不断发展和进步,交通事故、建筑工伤、自然灾害频繁发生,创伤仍然是全球一项重大的卫生与社会问题。严重创伤的高病死率和致残率给社会及个人带来巨大的经济和精神负担。近年来研究表明雌激素可能在严重创伤进程中扮演重要角色,一系列临床调查研究表明女性严重创伤患者病死率、并发症发生率显著低于男性;基于严重创伤动物模型的实验研究也为性别相关的结果差异提供了初步证据,但结果并不完全一致。然而严重创伤病理生理学机制涉及多个方面和环节,至今尚未完全清楚。笔者就雌激素及雌激素受体(estrogen receptor,ER)信号转导途径在严重创伤中的作用及机制综述如下。
Though so much social progress has been made continuously and rapidly in recent decades,trauma remains a major global health and social problem,mainly because of natural disaster,industrial construction,traffic accidents,and so on. Severe trauma of high mortality and morbidity brings about enormous economic and emotional burden for society and individuals. Some late studies have shown that estrogen may play an important role in the process of severe trauma,including clinical researches that suggested female patients with severe trauma had significantly lower mortality and complications,and experimental studies suggested significant gender-related differences in severe trauma,though controversies in details still eixt. However,the pathophysiological mechanism of severe trauma involves many aspects and links,which is still unclear. This paper reviewed the role and mechanism of estrogen and estrogen receptor signaling pathways in severe trauma.
Though so much social progress has been made continuously and rapidly in recent decades,trauma remains a major global health and social problem,mainly because of natural disaster,industrial construction,traffic accidents,and so on. Severe trauma of high mortality and morbidity brings about enormous economic and emotional burden for society and individuals. Some late studies have shown that estrogen may play an important role in the process of severe trauma,including clinical researches that suggested female patients with severe trauma had significantly lower mortality and complications,and experimental studies suggested significant gender-related differences in severe trauma,though controversies in details still eixt. However,the pathophysiological mechanism of severe trauma involves many aspects and links,which is still unclear. This paper reviewed the role and mechanism of estrogen and estrogen receptor signaling pathways in severe trauma.
引文
[1] 中国医师协会创伤外科医师分会,中华医学会创伤学分会创伤急救与多发伤学组,刘良明,等.创伤失血性休克早期救治规范[J].创伤外科杂志,2017,19(12):881-883,891.
[2] Ning P,Cai M,Cheng P,et al.Trends in injury morbidity in China,1993-2013: a longitudinal analysis of population-based survey data[J].Accid Anal Prev,2018,113:179-186.
[3] Sperry JL,Vodovotz Y,Ferrell RE,et al.Racial disparities and sex-based outcomes differences after severe injury[J].J Am Coll Surg,2012,214(6):973-980.
[4] Trentzsch H,Lefering R,Nienaber U,et al.The role of biological sex in severely traumatized patients on outcomes:a matched-pair analysis[J].Ann Surg,2015,261(4):774-780.
[5] Nagata I,Abe T,Uchida M,et al.Ten-year inhospital mortality trends for patients with trauma in Japan:a multicentre observational study[J].BMJ Open,2018,8(2):e018635.
[6] Zhu Z,Shang X,Qi P,et al.Sex-based differences in outcomes after severe injury:an analysis of blunt trauma patients in China[J].Scand J Trauma Resus Emerg Med,2017,25(1):47-54.
[7] 杨开超,耿磊,朱晓光,等.性激素水平可能是严重创伤患者预后性别差异的重要影响因素[J].中华急诊医学杂志,2015,24(3):304-309.
[8] Hubbard W,Keith J,Berman J,et al.17a-Ethynylestradiol-3-sulfate treatment of severe blood loss in rats[J].J Surg Res,2015,193(1):355-360.
[9] Doucet D,Badami C,Palange D,et al.Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats[J].PloS One,2010,5(2):e9421.
[10] Magnotti LJ,Fischer PE,Zarzaur BL,et al.Impact of gender on outcomes after blunt injury: a definitive analysis of more than 36,000 trauma patients[J].J Am College Surg,2008,206(5):984-992.
[11] May AK,Dossett LA,Norris PR,et al.Estradiol is associated with mortality in critically ill trauma and surgical patients[J].Critical Care Med,2008,36(1):62-68.
[12] Schoeneberg C,Kauther MD,Hussmann B,et al.Gender-specific differences in severely injured patients between 2002 and 2011:data analysis with matched-pair analysis[J].Crit Care,2013,17(6):1-9.
[13] Liu T,Xie J,Yang F,et al.The influence of sex on outcomes in trauma patients:a meta-analysis[J].Am J Surg,2015,210(5):911-921.
[14] Haider AH,Crompton JG,Oyetunji T,et al.Females have fewer complications and lower mortality following trauma than similarly injured males:a risk adjusted analysis of adults in the National Trauma Data Bank[J].Surg,2009,146(2):308-315.
[15] Zolin SJ,Vodovotz Y,Forsythe RM,et al.The early evolving sex hormone environment is associated with significant outcome and inflammatory response differences after injury[J].J Trauma Acute Care Surg,2015,78(3):451-457.
[16] Trentzsch H,Nienaber U,Behnke M,et al.Female sex protects from organ failure and sepsis after major trauma haemorrhage[J].Injury,2014,45(S3):20-28.
[17] Frink M,Pape HC,Van Griensven M,et al.Influence of sex and age on mods and cytokines after multiple injuries[J].Shock,2007,27(2):151-156.
[18] Kim H,Chen J,Zinn KR,et al.Single photon emission computed tomography demonstrated efficacy of 17beta-estradiol therapy in male rats after trauma-hemorrhage and extended hypotension[J].J Trauma,2010,69(5):1266-1273.
[19] Childs EW,Tharakan B,Hunter FA,et al.17beta-estradiol mediated protection against vascular leak after hemorrhagic shock:role of estrogen receptors and apoptotic signaling[J].Shock(Augusta,Ga),2010,34(3):229-235.
[20] Kim KH,Young BD,Bender JR.Endothelial estrogen receptor isoforms and cardiovascular disease[J].Mol Cell Endocrinol,2014,389(1-2):65-70.
[21] Prossnitz ER,Barton M.Estrogen biology:new insights into GPER function and clinical opportunities[J].Mol Cell Endocrinol,2014,389(1-2):71-83.
[22] Trenti A,Tedesco S,Boscaro C,et al.Estrogen,angiogenesis,immunity and cell metabolism: solving the puzzle[J].Inter J Molecular Sci,2018,19(3):859-875.
[23] Soliman M.Protective effects of estradiol on myocardial contractile function following hemorrhagic shock and resuscitation in rats[J].Chin Med J,2015,128(17):2360-2364.
[24] Hu S,Yang S,Cam B,et al.The estrogen receptor (er)-beta agonist, dpn, is more effective in improving cardiac function, cardiac estrogen receptor (ers),and estrogen related receptor(errs) expression than the estrogen receptor(er)-alpha agonist,ppt following trauma-hemorrhage; proceedings of the Shock,F 2015[C].Lippincott Williams & Wilkins Two Commerce SQ,2001 Market ST,Philadelphia,PA 19103 USA.
[25] Yang S,Hu S,Hubbard WJ,et al.Ethinyl estradiol-3-so4 (ee-3-so4) improves cardiovascular functions after trauma-hemorrhage (th) in the absence of fluid resuscitation by normalizing aortic inos expression/plasma nitrate/nitrite levels; proceedings of the shock (augusta, ga), F,2018[C].Lippincott Williams & Wilkins Two Commerce SQ,2001 Market ST,Philadelphia,PA 19103 USA.
[26] Deitch EA,Chu H,Xu DZ.Organ blood flow and the central hemodynamic response are better preserved in female,as opposed to the male rats,after trauma-hemorrhagic shock[J].J Trauma,2008,65(3):566-572.
[27] Li T,Xiao X,Zhang J,et al.Age and sex differences in vascular responsiveness in healthy and trauma patients:contribution of estrogen receptor-mediated Rho kinase and PKC pathways[J].Am J Physiol Heart Circ Physiol,2014,306(8):1105-1115.
[28] Hsu JT,Kan WH,Hsieh CH,et al.Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage:p38 MAPK-dependent upregulation of HO-1[J].Am J Physiol Regul Integr Comp Physiol,2008,294(6):1825-1831.
[29] Hsu JT,Kan WH,Hsieh CH,et al.Mechanism of salutary effects of estrogen on cardiac function following trauma-hemorrhage:Akt-dependent HO-1 up-regulation[J].Crit Care Med,2009,37(8):2338-2344.
[30] Hsieh YC,Frink M,Thobe BM,et al.17Beta-estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage[J].Molecular Immunol,2007,44(9):2165-2172.
[31] Gee AC,Sawai RS,Differding J,et al.The influence of sex hormones on coagulation and inflammation in the trauma patient[J].Shock(Augusta,Ga),2008,29(3):334-341.
[32] Lopez MC,Efron PA,Ozrazgat-Baslanti T,et al.Sex-based differences in the genomic response,innate immunity,organ dysfunction,and clinical outcomes after severe blunt traumatic injury and hemorrhagic shock[J].J Trauma Acute Care Surg,2016,81(3):478-485.
[33] Spolarics Z,Pena G,Qin Y,et al.Inherent X-linked genetic variability and cellular mosaicism unique to females contribute to sex-related differences in the innate immune response[J].Front Immunol,2017,1455(8):1-13.
[34] Pena G,Michalski C,Donnelly RJ,et al.Trauma-induced acute X chromosome skewing in white blood cells represents an immuno-modulatory mechanism unique to females and a likely contributor to sex-based outcome differences[J].Shock,2017,47(4):402-408.
[35] Sperry JL,Zolin S,Zuckerbraun BS,et al.X chromosome-linked IRAK-1 polymorphism is a strong predictor of multiple organ failure and mortality postinjury[J].Ann Surg,2014,260(4):698-703.
[36] Holloway TL,Nicholson SE,Rani M,et al.Toll-like receptor responses are suppressed in trauma ICU patients[J].J Surg Res,2016,206(1):139-145.
[2] Ning P,Cai M,Cheng P,et al.Trends in injury morbidity in China,1993-2013: a longitudinal analysis of population-based survey data[J].Accid Anal Prev,2018,113:179-186.
[3] Sperry JL,Vodovotz Y,Ferrell RE,et al.Racial disparities and sex-based outcomes differences after severe injury[J].J Am Coll Surg,2012,214(6):973-980.
[4] Trentzsch H,Lefering R,Nienaber U,et al.The role of biological sex in severely traumatized patients on outcomes:a matched-pair analysis[J].Ann Surg,2015,261(4):774-780.
[5] Nagata I,Abe T,Uchida M,et al.Ten-year inhospital mortality trends for patients with trauma in Japan:a multicentre observational study[J].BMJ Open,2018,8(2):e018635.
[6] Zhu Z,Shang X,Qi P,et al.Sex-based differences in outcomes after severe injury:an analysis of blunt trauma patients in China[J].Scand J Trauma Resus Emerg Med,2017,25(1):47-54.
[7] 杨开超,耿磊,朱晓光,等.性激素水平可能是严重创伤患者预后性别差异的重要影响因素[J].中华急诊医学杂志,2015,24(3):304-309.
[8] Hubbard W,Keith J,Berman J,et al.17a-Ethynylestradiol-3-sulfate treatment of severe blood loss in rats[J].J Surg Res,2015,193(1):355-360.
[9] Doucet D,Badami C,Palange D,et al.Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats[J].PloS One,2010,5(2):e9421.
[10] Magnotti LJ,Fischer PE,Zarzaur BL,et al.Impact of gender on outcomes after blunt injury: a definitive analysis of more than 36,000 trauma patients[J].J Am College Surg,2008,206(5):984-992.
[11] May AK,Dossett LA,Norris PR,et al.Estradiol is associated with mortality in critically ill trauma and surgical patients[J].Critical Care Med,2008,36(1):62-68.
[12] Schoeneberg C,Kauther MD,Hussmann B,et al.Gender-specific differences in severely injured patients between 2002 and 2011:data analysis with matched-pair analysis[J].Crit Care,2013,17(6):1-9.
[13] Liu T,Xie J,Yang F,et al.The influence of sex on outcomes in trauma patients:a meta-analysis[J].Am J Surg,2015,210(5):911-921.
[14] Haider AH,Crompton JG,Oyetunji T,et al.Females have fewer complications and lower mortality following trauma than similarly injured males:a risk adjusted analysis of adults in the National Trauma Data Bank[J].Surg,2009,146(2):308-315.
[15] Zolin SJ,Vodovotz Y,Forsythe RM,et al.The early evolving sex hormone environment is associated with significant outcome and inflammatory response differences after injury[J].J Trauma Acute Care Surg,2015,78(3):451-457.
[16] Trentzsch H,Nienaber U,Behnke M,et al.Female sex protects from organ failure and sepsis after major trauma haemorrhage[J].Injury,2014,45(S3):20-28.
[17] Frink M,Pape HC,Van Griensven M,et al.Influence of sex and age on mods and cytokines after multiple injuries[J].Shock,2007,27(2):151-156.
[18] Kim H,Chen J,Zinn KR,et al.Single photon emission computed tomography demonstrated efficacy of 17beta-estradiol therapy in male rats after trauma-hemorrhage and extended hypotension[J].J Trauma,2010,69(5):1266-1273.
[19] Childs EW,Tharakan B,Hunter FA,et al.17beta-estradiol mediated protection against vascular leak after hemorrhagic shock:role of estrogen receptors and apoptotic signaling[J].Shock(Augusta,Ga),2010,34(3):229-235.
[20] Kim KH,Young BD,Bender JR.Endothelial estrogen receptor isoforms and cardiovascular disease[J].Mol Cell Endocrinol,2014,389(1-2):65-70.
[21] Prossnitz ER,Barton M.Estrogen biology:new insights into GPER function and clinical opportunities[J].Mol Cell Endocrinol,2014,389(1-2):71-83.
[22] Trenti A,Tedesco S,Boscaro C,et al.Estrogen,angiogenesis,immunity and cell metabolism: solving the puzzle[J].Inter J Molecular Sci,2018,19(3):859-875.
[23] Soliman M.Protective effects of estradiol on myocardial contractile function following hemorrhagic shock and resuscitation in rats[J].Chin Med J,2015,128(17):2360-2364.
[24] Hu S,Yang S,Cam B,et al.The estrogen receptor (er)-beta agonist, dpn, is more effective in improving cardiac function, cardiac estrogen receptor (ers),and estrogen related receptor(errs) expression than the estrogen receptor(er)-alpha agonist,ppt following trauma-hemorrhage; proceedings of the Shock,F 2015[C].Lippincott Williams & Wilkins Two Commerce SQ,2001 Market ST,Philadelphia,PA 19103 USA.
[25] Yang S,Hu S,Hubbard WJ,et al.Ethinyl estradiol-3-so4 (ee-3-so4) improves cardiovascular functions after trauma-hemorrhage (th) in the absence of fluid resuscitation by normalizing aortic inos expression/plasma nitrate/nitrite levels; proceedings of the shock (augusta, ga), F,2018[C].Lippincott Williams & Wilkins Two Commerce SQ,2001 Market ST,Philadelphia,PA 19103 USA.
[26] Deitch EA,Chu H,Xu DZ.Organ blood flow and the central hemodynamic response are better preserved in female,as opposed to the male rats,after trauma-hemorrhagic shock[J].J Trauma,2008,65(3):566-572.
[27] Li T,Xiao X,Zhang J,et al.Age and sex differences in vascular responsiveness in healthy and trauma patients:contribution of estrogen receptor-mediated Rho kinase and PKC pathways[J].Am J Physiol Heart Circ Physiol,2014,306(8):1105-1115.
[28] Hsu JT,Kan WH,Hsieh CH,et al.Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage:p38 MAPK-dependent upregulation of HO-1[J].Am J Physiol Regul Integr Comp Physiol,2008,294(6):1825-1831.
[29] Hsu JT,Kan WH,Hsieh CH,et al.Mechanism of salutary effects of estrogen on cardiac function following trauma-hemorrhage:Akt-dependent HO-1 up-regulation[J].Crit Care Med,2009,37(8):2338-2344.
[30] Hsieh YC,Frink M,Thobe BM,et al.17Beta-estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage[J].Molecular Immunol,2007,44(9):2165-2172.
[31] Gee AC,Sawai RS,Differding J,et al.The influence of sex hormones on coagulation and inflammation in the trauma patient[J].Shock(Augusta,Ga),2008,29(3):334-341.
[32] Lopez MC,Efron PA,Ozrazgat-Baslanti T,et al.Sex-based differences in the genomic response,innate immunity,organ dysfunction,and clinical outcomes after severe blunt traumatic injury and hemorrhagic shock[J].J Trauma Acute Care Surg,2016,81(3):478-485.
[33] Spolarics Z,Pena G,Qin Y,et al.Inherent X-linked genetic variability and cellular mosaicism unique to females contribute to sex-related differences in the innate immune response[J].Front Immunol,2017,1455(8):1-13.
[34] Pena G,Michalski C,Donnelly RJ,et al.Trauma-induced acute X chromosome skewing in white blood cells represents an immuno-modulatory mechanism unique to females and a likely contributor to sex-based outcome differences[J].Shock,2017,47(4):402-408.
[35] Sperry JL,Zolin S,Zuckerbraun BS,et al.X chromosome-linked IRAK-1 polymorphism is a strong predictor of multiple organ failure and mortality postinjury[J].Ann Surg,2014,260(4):698-703.
[36] Holloway TL,Nicholson SE,Rani M,et al.Toll-like receptor responses are suppressed in trauma ICU patients[J].J Surg Res,2016,206(1):139-145.