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通讯作者:

殷善开(1964-),男,江苏射阳人,博士生导师,主要从事听觉、前庭及睡眠呼吸疾病方面的研究。E-mail:yinshankai@china.com

中图分类号:R722.17,R363.2+1

文献标识码:A

文章编号:2096-8965(2020)01-0096-03

DOI:10.12287/j.issn.2096-8965.20200116

参考文献 1
BHUTANI V K,JOHNSON L,SIVIERI E M.Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns[J].Pediatrics,1999,103(1):6-14.
参考文献 2
WATCHKO J F,TIRIBELLI C.Bilirubin-induced neurologic damage-mechanisms and management approaches[J].N Engl J Med,2013,369(21):2021-2030.
参考文献 3
OGUNLESI T A,DEDEKE I O,ADEKANMBI A F,etal.The incidence and outcome of bilirubin encephalopathy in Nigeria:a bi-centre study[J].Niger J Med,2007,16(4):354-359.
参考文献 4
LAWN J E,BLENCOWE H,OZA S,et al.Every Newborn:progress,priorities,and potential beyond survival[J].Lancet,2014,384(9938):189-205.
参考文献 5
LASKY R E,CHURCH M W,ORLANDO M S,et al.The effects of aggressive vs.conservative phototherapy on the brainstem auditory evoked responses of extremelylow-birth-weight infants[J].Pediatr Res,2012,71(1):77-84.
参考文献 6
HANSEN T W.Mechanisms of bilirubin toxicity:clinical implications[J].Clin Perinatol,2002,29(4):765-778.
参考文献 7
POSNER J B,PLUM F.Spinal-fluid pH and neurologic symptoms in systemic acidosis[J].N Engl J Med,1967,277(12):605-613.
参考文献 8
DENNERY P A,SEIDMAN D S,STEVENSON D K.Neonatal hyperbilirubinemia[J].N Engl J Med,2001,344(8):581-590.
参考文献 9
AMIN S B,AHLFORS C,ORLANDO M S,et al.Bilirubin and serial auditory brainstem responses in premature infants[J].Pediatrics,2001,107(4):664-670.
参考文献 10
WATCHKO J F.Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns[J].Neuromolecular Med,2006,8(4):513-529.
参考文献 11
SHI H B,KAKAZU Y,SHIBATA S,et al.Bilirubin potentiates inhibitory synaptic transmission in lateral superior olive neurons of the rat[J].Neurosci Res,2006,55(2):161-170.
参考文献 12
LI C Y,SHI H B,SONG N Y,et al.Bilirubin enhances neuronal excitability by increasing glutamatergic transmission in the rat lateral superior olive[J].Toxicology,2011,284(1/3):19-25.
参考文献 13
LIANG M,YIN X L,SHI H B,et al.Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels[J].Sci Rep,2017,7(1):431.
参考文献 14
YIN X L,LIANG M,SHI H B,et al.The role of gammaaminobutyric acid/glycinergic synaptic transmission in mediating bilirubin-induced hyperexcitation in developing auditory neurons[J].Toxicol Lett,2016,240(1):1-9.
参考文献 15
JEROME B,POSNER F P.Spinal-fluid pH and neurologic symptoms in systemic acidosis[J].N Engl J Med,1967,277(12):605-613.
参考文献 16
LIU J,LONG J,ZHANG S,et al.The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia:a systematic review with meta-analysis[J].J Pediatr(Rio J),2013,89(5):434-443.
参考文献 17
TIWARI P K,BHUTADA A,AGARWAL R,et al.UGT1A1 gene variants and clinical risk factors modulate hyperbilirubinemia risk in newborns[J].J Perinatol,2014,34(2):120-124.
目录contents
  • 前言

  • 新生儿高胆红素血症(Hyperbilirubinemia) 亦称为新生儿黄疸,出现于约85%的新生儿[1],尤以包括我国在内的一些发展中国家为甚,其发病率可高于发达国家的100倍之多[2]。在发展中国家当中, 约有3%的住院新生儿经历了不同程度的急性黄疸症状,由高胆红素血症导致的核黄疸,其致死率和破伤风相差无几[3]。全球每年至少有48万例新生儿出现胆红素神经毒性症状,大量患儿遗留不同程度的听觉、平衡、认知等中枢神经系统功能损害[4]。 传统观点认为血清胆红素浓度的高低是黄疸严重程度的首要评估标准。但近年来,在临床诊疗中观察到,血清胆红素浓度较高的“病理性黄疸”并不一定出现中枢神经损害;同时,在血清胆红素浓度并不高的“生理性黄疸”新生儿当中,也可出现严重的中枢神经系统症状[5],这提示,除了胆红素浓度这一危险因素之外,还有其他潜在因素参与损害机制。

  • 临床发现多种危险因素与新生儿黄疸所致的中枢神经损害的发生、发展相关,其中尤以酸中毒最为突显[6]。酸中毒常由胎儿宫内窘迫、出生后呼吸困难、感染等所致,也是新生儿期最为常见的临床症状之一。当各种原因(缺血、缺氧、感染等) 引致酸中毒时,血液的pH值可下降至6.5 甚至6 以下。与血液不同的是,由于血脑屏障及更强缓冲系统的存在,脑脊液pH值通常维持在一个相对稳定的状态(pH 7.3~7.4)。但在持续酸中毒时,H+ 大量渗透过血脑屏障,随着缓冲物质的消耗,脑脊液的pH可下降至6.8~7.0[7]。既往临床观察到,黄疸患儿在合并酸中毒的数小时后即可出现“亚临床型” 胆红素神经毒性症状,随后很快演变为明显的神经系统损害;若及时进行纠酸治疗,可使神经电生理指标恢复正常,或者减轻其严重程度[8]。类似的研究发现,新生儿发生黄疸时,若积极防治酸中毒, 能够预防脑干听觉诱发电位(Brainstem Auditory Evoked Potential,BAEP)的异常,以及预防胆红素脑病的发生[9]。对于酸中毒加剧胆红素神经毒性的临床现象,传统观点认为酸中毒可以破坏血脑屏障,使得胆红素更易进入脑内,导致过量的胆红素沉积而引起毒性作用[10]

  • 酸敏感离子通道(Acid-sensing Ion Channels, ASICs) 在中枢神经系统广泛分布,脑脊液pH值的细微下降即可激活ASICs,后者通过介导阳离子内流而诱发细胞膜去极化,这将导致膜表面各种电压门控通道的激活,由此引发一系列细胞内环境病理改变,从而导致神经元毒性。对于胆红素神经毒性机制而言,我们既往研究表明[11-14],胆红素通过促进谷氨酸神经递质释放、上调钙离子通道活性等途径,诱发神经元兴奋毒性。由于H+ 与胆红素均可导致神经兴奋毒性,提示了神经元的兴奋毒性可能是酸中毒与黄疸联合导致严重中枢损害的基础。

  • 1 黄疸合并酸中毒新生儿的临床资料分析

  • 鉴于既往缺乏新生儿黄疸合并酸中毒所致中枢损害的临床生化研究数据,本课题组搜集了2014 年6月至2017年6月期间上海交通大学附属上海市儿童医院(合作单位) 所有进行过脑脊液检查的患儿临床资料,分析了黄疸与酸中毒患儿脑脊液生化、血气、血生化各个指标之间的关系,以脑脊液乳酸脱氢酶(Lactic Dehydrogenase,LDH) 作为中枢神经元损伤程度评估指标。上述临床数据分析结果清晰显示,黄疸合并酸中毒时更易出现严重的中枢神经元损伤,且脑脊液LDH与血胆红素浓度、 血液pH值密切相关,其潜在机制亟待破解,以期指导临床诊治。

  • 2 胆红素与酸敏感离子通道的基础研究

  • 我们的临床数据分析结果及既往研究提示,胆红素可能与ASICs存在某种协同作用,可导致神经元兴奋毒性和细胞死亡。通过膜片钳、Co-IP、钙成像、活脑片细胞死亡染色等技术进行的体外基础实验表明,在微弱的酸性(例如pH 7.0) 条件下, 胆红素对神经的毒性作用将显著增加:胆红素通过促进ASICs活性导致神经元过度兴奋,[Ca2+ ]i超载和细胞死亡(LDH释放)。更重要的是,胆红素的作用最适pH值为7.0~7.3,这与既往报道的酸中毒新生儿的脑脊液pH值一致[15]。我们的发现提示了临床治疗黄疸时监测新生儿血气pH值的重要价值。

  • 3 黄疸合并酸中毒动物模型的在体研究

  • 我们的前述研究已阐述其体外机制——胆红素通过促进ASICs的活性来增加神经元兴奋性,从而导致细胞死亡。为了进一步验证前期研究,我们进行了一系列在体研究——通过建立黄疸合并酸中毒的动物模型,并进行与不同脑区的功能相关的行为学实验,来揭示发育早期的胆红素神经毒性对远期神经功能的影响。缺氧诱发酸中毒的新生小鼠表现出血脑屏障通透性的增加,这就证实了酸增强了胆红素进入大脑的可能性,并使其沉积以发挥神经毒性作用。我们的神经行为学实验表明:黄疸合并酸中毒模型小鼠在空间记忆、感觉、运动功能和听力方面表现出更严重的功能障碍。由于这些行为学实验的结果取决于ASICs广泛表达且胆红素易沉积的海马、小脑和脑干(包括前庭和听觉核) 等区域,因此我们的研究结果证实了胆红素和ASICs在导致发育早期脑损伤中起协同毒性作用的观点,即黄疸合并酸中毒可以导致远期神经功能障碍表现。

  • 总而言之,我们开展临床与基础相结合的转化医学研究模式,从临床数据分析中发现黄疸合并酸中毒加重脑损伤的证据。胆红素的神经毒性通过增强ASICs活性,导致神经元超兴奋和[Ca2+ ]i超载, 胞内Ca2+ 浓度超出了新生神经元的代偿能力,最终造成神经元损伤以及远期的感觉和认知障碍。我们的研究提示,保护神经元免受兴奋毒性损伤,需要注意监测黄疸患儿的脑脊液LDH和pH[16, 17],并进行及时的纠酸治疗,ASICs可能是治疗黄疸合并酸中毒的靶标之一,酸中毒是黄疸诱发中枢损伤的重要危险因素,并首次揭示了ASICs在新生儿黄疸中的重要意义。本研究在国家自然科学基金委的资助下,以赖轲为第一作者,上海交通大学医学院徐天乐教授团队的宋兴磊为共同第一作者,时海波、殷善开为通讯作者,于2020年2月12日在线发表于国际转化医学顶级刊物Science Translational Medicine。

  • 参考文献

    • [1] BHUTANI V K,JOHNSON L,SIVIERI E M.Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns[J].Pediatrics,1999,103(1):6-14.

    • [2] WATCHKO J F,TIRIBELLI C.Bilirubin-induced neurologic damage-mechanisms and management approaches[J].N Engl J Med,2013,369(21):2021-2030.

    • [3] OGUNLESI T A,DEDEKE I O,ADEKANMBI A F,etal.The incidence and outcome of bilirubin encephalopathy in Nigeria:a bi-centre study[J].Niger J Med,2007,16(4):354-359.

    • [4] LAWN J E,BLENCOWE H,OZA S,et al.Every Newborn:progress,priorities,and potential beyond survival[J].Lancet,2014,384(9938):189-205.

    • [5] LASKY R E,CHURCH M W,ORLANDO M S,et al.The effects of aggressive vs.conservative phototherapy on the brainstem auditory evoked responses of extremelylow-birth-weight infants[J].Pediatr Res,2012,71(1):77-84.

    • [6] HANSEN T W.Mechanisms of bilirubin toxicity:clinical implications[J].Clin Perinatol,2002,29(4):765-778.

    • [7] POSNER J B,PLUM F.Spinal-fluid pH and neurologic symptoms in systemic acidosis[J].N Engl J Med,1967,277(12):605-613.

    • [8] DENNERY P A,SEIDMAN D S,STEVENSON D K.Neonatal hyperbilirubinemia[J].N Engl J Med,2001,344(8):581-590.

    • [9] AMIN S B,AHLFORS C,ORLANDO M S,et al.Bilirubin and serial auditory brainstem responses in premature infants[J].Pediatrics,2001,107(4):664-670.

    • [10] WATCHKO J F.Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns[J].Neuromolecular Med,2006,8(4):513-529.

    • [11] SHI H B,KAKAZU Y,SHIBATA S,et al.Bilirubin potentiates inhibitory synaptic transmission in lateral superior olive neurons of the rat[J].Neurosci Res,2006,55(2):161-170.

    • [12] LI C Y,SHI H B,SONG N Y,et al.Bilirubin enhances neuronal excitability by increasing glutamatergic transmission in the rat lateral superior olive[J].Toxicology,2011,284(1/3):19-25.

    • [13] LIANG M,YIN X L,SHI H B,et al.Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels[J].Sci Rep,2017,7(1):431.

    • [14] YIN X L,LIANG M,SHI H B,et al.The role of gammaaminobutyric acid/glycinergic synaptic transmission in mediating bilirubin-induced hyperexcitation in developing auditory neurons[J].Toxicol Lett,2016,240(1):1-9.

    • [15] JEROME B,POSNER F P.Spinal-fluid pH and neurologic symptoms in systemic acidosis[J].N Engl J Med,1967,277(12):605-613.

    • [16] LIU J,LONG J,ZHANG S,et al.The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia:a systematic review with meta-analysis[J].J Pediatr(Rio J),2013,89(5):434-443.

    • [17] TIWARI P K,BHUTADA A,AGARWAL R,et al.UGT1A1 gene variants and clinical risk factors modulate hyperbilirubinemia risk in newborns[J].J Perinatol,2014,34(2):120-124.

  • 参考文献

    • [1] BHUTANI V K,JOHNSON L,SIVIERI E M.Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns[J].Pediatrics,1999,103(1):6-14.

    • [2] WATCHKO J F,TIRIBELLI C.Bilirubin-induced neurologic damage-mechanisms and management approaches[J].N Engl J Med,2013,369(21):2021-2030.

    • [3] OGUNLESI T A,DEDEKE I O,ADEKANMBI A F,etal.The incidence and outcome of bilirubin encephalopathy in Nigeria:a bi-centre study[J].Niger J Med,2007,16(4):354-359.

    • [4] LAWN J E,BLENCOWE H,OZA S,et al.Every Newborn:progress,priorities,and potential beyond survival[J].Lancet,2014,384(9938):189-205.

    • [5] LASKY R E,CHURCH M W,ORLANDO M S,et al.The effects of aggressive vs.conservative phototherapy on the brainstem auditory evoked responses of extremelylow-birth-weight infants[J].Pediatr Res,2012,71(1):77-84.

    • [6] HANSEN T W.Mechanisms of bilirubin toxicity:clinical implications[J].Clin Perinatol,2002,29(4):765-778.

    • [7] POSNER J B,PLUM F.Spinal-fluid pH and neurologic symptoms in systemic acidosis[J].N Engl J Med,1967,277(12):605-613.

    • [8] DENNERY P A,SEIDMAN D S,STEVENSON D K.Neonatal hyperbilirubinemia[J].N Engl J Med,2001,344(8):581-590.

    • [9] AMIN S B,AHLFORS C,ORLANDO M S,et al.Bilirubin and serial auditory brainstem responses in premature infants[J].Pediatrics,2001,107(4):664-670.

    • [10] WATCHKO J F.Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns[J].Neuromolecular Med,2006,8(4):513-529.

    • [11] SHI H B,KAKAZU Y,SHIBATA S,et al.Bilirubin potentiates inhibitory synaptic transmission in lateral superior olive neurons of the rat[J].Neurosci Res,2006,55(2):161-170.

    • [12] LI C Y,SHI H B,SONG N Y,et al.Bilirubin enhances neuronal excitability by increasing glutamatergic transmission in the rat lateral superior olive[J].Toxicology,2011,284(1/3):19-25.

    • [13] LIANG M,YIN X L,SHI H B,et al.Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels[J].Sci Rep,2017,7(1):431.

    • [14] YIN X L,LIANG M,SHI H B,et al.The role of gammaaminobutyric acid/glycinergic synaptic transmission in mediating bilirubin-induced hyperexcitation in developing auditory neurons[J].Toxicol Lett,2016,240(1):1-9.

    • [15] JEROME B,POSNER F P.Spinal-fluid pH and neurologic symptoms in systemic acidosis[J].N Engl J Med,1967,277(12):605-613.

    • [16] LIU J,LONG J,ZHANG S,et al.The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia:a systematic review with meta-analysis[J].J Pediatr(Rio J),2013,89(5):434-443.

    • [17] TIWARI P K,BHUTADA A,AGARWAL R,et al.UGT1A1 gene variants and clinical risk factors modulate hyperbilirubinemia risk in newborns[J].J Perinatol,2014,34(2):120-124.

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