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医药导报, 2019, 38(5): 572-575
doi: 10.3870/j.issn.1004-0781.2019.05.008
重组人促红细胞生成素对早产贫血患儿神经行为发育和外周血白细胞介素表达的影响*
Effects of rh-EPO on Neurobehavioral Development and Expression of Peripheral Interleukin in Infants with Premature Anemia
何兴宇, 边朋, 张怡

摘要:

目的 观察重组人促红细胞生成素(rh-EPO)对早产贫血患儿神经行为发育和外周血单核细胞白细胞介素-17(IL-17)和白细胞介素-23(IL-23)表达的影响。方法 64例贫血早产儿随机分为治疗组和对照组,每组32例,两组均给予常规治疗,对照组在常规治疗的基础上,于出生后10 d服用铁剂,治疗组在对照组治疗的基础上皮下注射rh-EPO。治疗时间为5周。对两组患儿治疗前与治疗后4周进行NBNA评定,同时检测两组患儿外周血IL-17 mRNA和IL-23 mRNA的表达水平,治疗后12周对患儿进行Gesell评定。结果 治疗组与对照组治疗4周后均比治疗前NBNA评分高,差异有统计学意义(P<0.05),治疗组治疗4周后NBNA评分高于对照组,差异有统计学意义(P<0.05)。两组患儿治疗后4个月Gesell评定显示,治疗组粗大运动、精细运动、适应性行为、语言、个人-社会性行为得分均高于对照组(P<0.05)。治疗4周后治疗组与对照组前IL-17 mRNA和IL-23 mRNA相对表达量均低于治疗前(P<0.05),治疗组治疗4周后IL-17 mRNA和IL-23 mRNA相对表达量均低于对照组(P<0.05)。结论 rh-EPO有助于贫血早产儿神经行为的发育,对脑损伤有一定的保护作用,可降低IL-17和IL-23促炎细胞因子的表达。

关键词: 重组人促红细胞生成素 ; 早产儿 ; 贫血 ; 白细胞介素

Abstract:

Objective To investigate the effects of recombinant human erythropoietin(rh-EPO) on neurobehavioral development and peripheral monocyte interleukin-17(IL-17) and interleukin-23(IL-23) expression in infants with premature anemia. Methods A total of 64 cases of anemia premature infants were randomly assigned to the treatment group and the control group (32 infants in each group).The control group were given routine treatment, on the basis of treatment,iron was given 10 days after birth. The treatment group was given subcutaneous injection of rh-EPO on the besides the treatment of control group.Treatment time was 5 weeks. The neonatal behavioral neurological assessment (NBNA) was performed before and 4 weeks after treatment in both groups.The Gesell developmental schedules was assessed 12 weeks after treatment. The levels of IL-17 mRNA and IL-23 mRNA in peripheral blood of the two groups were also measured. Results The NBNA scores of the treatment group and the control group at 4 weeks after treatment were higher than the pre-treatment,and the difference was statistically significant(P<0.05).The NBNA score of the treatment group was higher than that of the control group at 4 weeks after treatment(P<0.05). The Gesell's assessment showed that the gross weight,fine motor,adaptive behavior,language,and individual-social behavior scores of the treatment group were higher than those of the control group(P<0.05).The relative expressions of IL-17 mRNA and IL-23 mRNA in the treatment group and the control group were lower than those before treatment at 4 weeks after treatment,and the difference was statistically significant(P<0.05).The levels of IL-17 mRNA and IL-23 mRNA were measured in the treatment group 4 weeks after treatment.The relative expression levels were lower than the control group,and the difference was statistically significant(P<0.05). Conclusion rh-EPO contributes to the development of neurobehavior in premature infants with anemia,and has a protective effect on brain injury,which can reduce the expression of IL-17 and IL-23 proinflammatory cytokines.

Key words: Recombinant human erythropoietin ; Premature infant ; Anemia ; Interleukin

促红细胞生成素(erythropoietin,EPO)是一种主要是由肾脏和肝脏分泌的活性糖蛋白,可以通过与红细胞上特异性EPO受体结合,从而促进红细胞增殖、分化、成熟[1,2]。重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)具有促进红系造血祖细胞的分化、促进红细胞生成的作用,还是一种神经营养因子,可改善由多种原因所导致的脑损伤,可改善脑损伤导致的认知学习损害、神经行为发育障碍[3]。对于临床早产儿贫血情况以往通常多采用补充铁剂治疗,但随着医学技术的进步,rh-EPO已成为治疗新生儿贫血的新方法。目前国内外研究中rh-EPO对于外周血单核细胞IL-17和IL-23的表达影响的研究较少,因此,2015年7月—2017年9月本研究通过对rh-EPO治疗后的患儿的外周血单核细胞IL-17和IL-23表达的变化,来探究其关联性,报道如下。

1 资料与方法
1.1 临床资料

纳入标准:胎龄<37周;出生体质量1000~2000 g;头围<33 cm;头颅B超检查有脑损伤。排除标准:合并先天性心脏病;感染性疾病;研究前使用过rh-EPO治疗;不符合早产儿诊断标准。选取我院收治的早产儿64例作为研究对象。所有患儿均符合《实用新生儿学》[4]中早产儿贫血诊断指标:生后 2 周内,末梢血血红蛋白(hemoglobin,Hb)≤145 g·L-1;生后 2 周至 1 个月,末梢血Hb<110 g·L-1;出生 1 个月后,末梢血Hb<90 g·L-1。其中男41例,女23例;胎龄28~35周,平均(31.2±2.3)周;体质量1510~1913 g,平均为(1732±180) g。将64例患儿简单随机分配为治疗组与对照组,每组32例。两组患儿性别、年龄、体质量等差异无统计学意义,具有可比性。本研究已通过我院伦理委员会批准,患儿家属均知情同意。

1.2 治疗方法

两组患儿均给予常规治疗,常规治疗包括维持水、电解质酸碱平衡,维持温度、呼吸和营养支持,并在出生后2~3 d给予脑活素2 mL·d-1,10 d为一个疗程。对照组在常规治疗的基础上,于出生后第10天开始服用琥珀酸亚铁(四川奥邦药业有限公司,批准文号:国药准字H20083003),根据元素铁6 mg·kg-1·d-1计算,并口服维生素C(四川衣科制药有限公司,批准文号:国药准字H51020297)0.2 g·d-1、维生素E(华润双鹤药业有限公司,批准文号:国药准字H11022348)25 mg·d-1。治疗组在对照组治疗的基础上皮下注射rh-EPO(沈阳三生制药有限公司,批准文号:国药准字201112186S)500 U·kg-1,每周3次。两组患儿治疗时间均为5周。

1.3 观察指标

新生儿神经行为评定[5](neonatal neurobehavioral assessment,NBNA):NBNA评分表共20个项目,每项最高2分,最低0分,总分为40分,当评分<35分时,提示新生儿有脑损伤。共分为5个部分,①行为能力,②被动肌张力,③主动肌张力,④原始反射,⑤一般估价。

Gesell发育量表[6]:评分包括粗大运动、精细运动、适应性行为、语言、个人社会性行为五项。

Apgar量表[7]:评分包括肌张力、脉搏、皱眉动作、外貌、呼吸五项,满10分为正常新生儿,小于7分考虑新生儿有轻度窒息,小于4分考虑患有重度窒息。

外周血IL-17、IL-23含量的检测:治疗前与治疗后4周抽取患儿空腹静脉血2 mL,置于抗凝管中,离心取上层清液,采用RT-PCR检测所有患者治疗前后外周单核细胞IL-17 mRNA和IL-23 mRNA相对表达量。

1.4 统计学方法

采用SPSS 20.0版软件对数据进行分析。计量资料采用均数±标准差表示,组间均数比较采用t检验,以P<0.05为差异有统计学意义。

2 结果
2.1 两组患儿一般资料的对比

两组患儿一般资料对比差异无统计学意义,研究具有可比性。见表1。

表1 两组患儿一般资料比较
Tab.1 Comparison of general data between two groups of infants x¯±s,n=32
组别 性别 出生
体质量/g
胎龄/
Apgar评分
1 min 5 min
对照组 21 11 1670.4±127.8 33.1±1.5 7.4±1.4 8.5±1.1
治疗组 20 12 1641.2±125.4 32.4±1.4 7.4±1.3 8.5±1.0

表1 两组患儿一般资料比较

Tab.1 Comparison of general data between two groups of infants x¯±s,n=32

2.2 两组患儿治疗前、治疗后4周神经行为发育情况比较

治疗组与对照组在治疗前NBNA评分差异无统计学意义(P>0.05),治疗组与对照组治疗后4周均比治疗前NBNA评分高,差异有统计学意义(P<0.05),治疗组治疗后4周NBNA评分高于对照组,差异有统计学意义(P<0.05)。见表2。

表2 治疗前后两组患儿NBNA评分比较
Tab.2 Comparison of NBNA scores between two groups of infants before and after treatment 分,x¯±s,n=32
组别 治疗前 治疗后4周
对照组 22.2±0.2 34.6±0.7
治疗组 22.1±0.4 38.1±1.5*1

与对照组比较,*1P<0.05

Compared with control group,*1P<0.05

表2 治疗前后两组患儿NBNA评分比较

Tab.2 Comparison of NBNA scores between two groups of infants before and after treatment 分,x¯±s,n=32

2.3 两组患儿治疗后12周Gesell发育量表比较

两组患儿治疗后4个月Gesell评定显示,治疗组粗大运动、精细运动、适应性行为、语言、个人—社会性行为得分均高于对照组,差异具有统计学意义(P<0.05)。见表3。

表3 两组患儿治疗后12周Gesell发育量表评分比较
Tab.3 Comparison of Gesell development scale between two groups of infants at 12 weeks after treatment 分,x¯±s,n=32
组别 粗大运动 精细运动 适应性行为
对照组 82.1±10.1 87.6±10.1 91.8±15.1
治疗组 88.1±10.5 93.1±10.5 100.7±19.3
t 2.329 2.136 2.055
P 0.023 0.037 0.044
组别 语言 个人-社会性行为
对照组 82.1±10.3 81.5±10.0
治疗组 90.1±8.5 87.1±10.5
t 3.389 2.185
P 0.001 0.033

表3 两组患儿治疗后12周Gesell发育量表评分比较

Tab.3 Comparison of Gesell development scale between two groups of infants at 12 weeks after treatment 分,x¯±s,n=32

2.4 两组患儿治疗前、治疗后4周IL-17 mRNA和IL-23 mRNA相对表达量的比较

两组患儿治疗前IL-17 mRNA和IL-23 mRNA相对表达量比较差异无统计学意义(P>0.05),治疗后4周治疗组与对照组前IL-17 mRNA和IL-23 mRNA相对表达量均低于治疗前,差异有统计学意义(P<0.05),治疗组治疗后4周IL-17 mRNA和IL-23 mRNA相对表达量均低于对照组,差异有统计学意义(P<0.05)。见表4。

表4 两组患儿外周血IL-17和IL-23相对表达量比较
Tab.4 Comparison of IL-17 and IL-23 relative expression in peripheral blood between two groups of infants bp,x¯±s,n=32
组别与时间 IL-17 IL-23
对照组
治疗前 0.5±0.1 0.4±0.1
治疗后4周 0.4±0.1 0.2±0.11
治疗组
治疗前 0.5±0.1 0.4±0.1
治疗后4周 0.2±0.1*1 0.1±0.1*1

与对照组比较,*1P<0.05

Compared with control group,*1P<0.05

表4 两组患儿外周血IL-17和IL-23相对表达量比较

Tab.4 Comparison of IL-17 and IL-23 relative expression in peripheral blood between two groups of infants bp,x¯±s,n=32

3 讨论
3.1 我国早产儿情况及早产儿贫血的治疗措施

早产儿是指胎龄小于37周的活产婴儿,其出生体质量大部分<2500 g,头围<33 cm。我国早产儿的发生率为9.9%,病死率为12.7%~20.8%,新生儿早产已发展成为我国新生儿死亡最主要原因。贫血是早产儿出生后最常见的并发症之一,贫血的发生率随着早产儿胎龄的减小而逐渐升高,胎龄越小,出现贫血的概率越高[8]。贫血会对早产儿生长发育造成巨大的影响,长时间贫血会使早产儿大脑缺血缺氧,从而导致脑损伤。目前临床上的治疗方法主要是以促红细胞生成素及铁剂类药物的使用为主[9]。早产儿EPO水平低是造成贫血的主要原因,临床上使用rh-EPO能有效解决早产儿的贫血情况。

3.2 rh-EPO对早产贫血患儿神经行为发育的影响

近年来,大量研究显示,EPO不仅可以用于治疗早产儿贫血,而且对中枢神经系统具有神经保护的作用[10,11,12]。董海鹏等[13]通过对胎龄<34周,出生体质量<2500 g的脑损伤早产儿194例研究发现,早产儿血清EPO水平越低,脑损伤的发生率越高,EPO对神经系统具有一定的保护作用,但EPO对神经系统保护作用的具体机制尚未明确。本研究结果显示,rh-EPO治疗后患儿NBNA评分要高于未经rh-EPO治疗的患儿,差异有统计学意义,这说明rh-EPO的使用有助于患儿神经行为发育,对患儿脑损伤有一定的保护作用。在本研究中,两组患儿在治疗后12周Gesell量表评分显示,治疗组粗大运动、精细运动、适应性行为、语言、个人-社会性行为得分均高于对照组,差异有统计学意义,这表明了rh-EPO对缺血缺氧所导致的神经系统发育损伤有一定的修复作用,可改善神经元功能[14,15,16]。有研究发现,新生小白鼠经过多次使用EPO可改善缺血缺氧后的神经发育问题,预防因缺血缺氧脑损伤所引起的多巴胺通路神经元消耗[17]。相关研究认为,EPO可通过减轻脑水肿程度、促进血管再生等发挥保护神经的作用[18]

3.3 rh-EPO对早产贫血患儿IL-17和IL-23表达水平的影响

IL-17是一种强大的促炎症因子,主要是由T细胞分泌的TH17细胞分泌产生,在防御外部细菌感染、引发炎症反应方面均发挥着作用。IL-23也是一种促进炎症反应的细胞因子,主要是由活化的巨噬细胞和树突状细胞分泌。IL-17,IL-23在急性神经炎症中发挥着一定的作用,IL-17的产生主要是依赖IL-23的调节,IL-23可以刺激C D 4 + 辅助性T细胞产生IL-17,具体机制目前尚未清楚。巨噬细胞分泌的IL-23促进了T淋巴细胞分泌IL-17可以加重脑损伤中的炎症反应[19]。病原体由血循环进入脑组织和脑室前会被完整的血-脑屏障所阻隔,但对于炎症细胞如何通过血-脑屏障,并引起大脑炎症反应,从而导致脑损伤,这其中的机制尚未完全清楚。本研究结果显示,两组患儿治疗前IL-17 mRNA相对表达量与IL-23 mRNA相对表达量差异无统计学意义。治疗组患儿在治疗后4周IL-17 mRNA和IL-23 mRNA相对表达量均低于对照组,差异有统计学意义。这说明了rh-EPO同样具有一定的抗炎作用,降低了IL-17和IL-23促炎细胞因子的表达。国外有关研究也显示,EPO具有减轻炎症反应的作用[20],本研究结果与之相一致。

综上所述,rh-EPO有助于贫血早产儿神经行为的发育,对脑损伤有一定的保护作用,可降低IL-17,IL-23促炎细胞因子的表达。

The authors have declared that no competing interests exist.

参考文献

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[3] 刘晓静,江莲.促红细胞生成素不同用药时机治疗早产儿贫血的效果研究[J].中国全科医学,2017,20(32):3991-3995.
目的探讨促红细胞生成素(EPO)在早产儿贫血中的治疗时机,以及对不同胎龄早产儿贫血的疗效。方法选取2014年3月—2016年2月于保定市妇幼保健院新生儿科收治的贫血早产儿90例为研究对象,采用抽签法分为对照组、晚治疗组及早治疗组,各30例。早治疗组和晚治疗组分别在出生第2周、3周开始每周给予EPO750 U/kg,并在应用EPO 1周后给予口服铁剂至出生后5周。对照组常规治疗,仅出生第2周开始给予口服铁剂至出生后5周。分别于各组治疗前及治疗后检测血红蛋白(Hb)、血细胞比容(HCT)、网织红细胞计数(Ret)、铁蛋白(SF)、叶酸、维生素B_(12)水平,记录各组治疗期间输血治疗例数。结果治疗后,晚治疗组Hb、HCT、Ret水平高于对照组,早治疗组Hb、HCT、Ret水平高于对照组、晚治疗组(P<0.05)。晚治疗组与早治疗组叶酸、维生素B_(12)治疗前后差值比较无差异(P>0.05),而早治疗组SF治疗前后差值高于晚治疗组(P<0.05)。早治疗组中,大胎龄儿与小胎龄儿治疗后叶酸、维生素B_(12)水平比较无差异(P>0.05),而大胎龄儿Hb、HCT、Ret、SF水平高于小胎龄儿(P<0.05)。治疗期间,对照组、晚治疗组、早治疗组输血率分别为63.3%(19/30)、43.3%(13/30)、36.7%(11/30),差异无统计学意义(P=0.099)。早治疗组中,小胎龄儿输血率(6/15)与大胎龄儿(5/15)比较,差异无统计学意义(P>0.05)。结论出生第2周早期应用EPO可改善早产儿贫血程度,且对大胎龄儿的治疗效果优于小胎龄儿,但尚不能完全避免输血。
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[4] 邵肖梅,叶鸿瑁,丘小汕.实用新生儿学[M].4版.北京:人民卫生出版社,2011:590-654.
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[5] 全国新生儿行为神经科研协作组,全国新生儿生长发育科研协作组.中国12城市正常新生儿20项行为神经评价[J].中华儿科杂志,1990,28(3):160.
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[7] 徐志华. 全麻药物在剖宫产中对新生儿Apgar评分及NBNA的影响[J].中国卫生标准管理,2016,7(15):177-178.
目的分析全身麻醉药物在剖宫产 中对新生儿Apgar评分及神经行为(NBNA)的影响。方法 84例择期剖宫产孕妇,随机分为硬膜外麻醉组、全身麻醉A组与全身麻醉B组,各28例,对比三组新生儿情况。结果三组新生儿娩出后1、5、10 min时Apgar评分组间对比,差异无统计学意义(P0.05),且随着时间的延长三组新生儿Apgar评分均显著升高,差异有统计学意义 (P0.05)。术后3、7 d三组新生儿NBNA评分组间对比,差异无统计学意义(P0.05)。结论全身麻醉药物用于剖宫产不会对新生儿的Apgar评分及NBNA造成影响,安全 性高,可推广应用。
[本文引用:1]
[8] 郝素芳,丁瑛雪,杨丽君,.影响早产儿贫血的相关因素分析[J].中国妇幼健康研究,2017,28(12):1503-1507.
目的 探讨影响和加重早产儿贫血的因素.方法 选择2012年1月至2013年6月在我院新生儿科住院期间出现贫血的早产儿,按不同胎龄、出生体重、出生时基础血红蛋白(Hb)值、有无机械通气进行分 组,分别比较各组贫血出现时间和住院期间Hb最低值.结果 胎龄<32周、出生体重<1500 g的早产儿,贫血出现时间分别为(12.9±5.0)天、(12.5±4.1)天,Hb最低值分别为(94.3±14.1)g/L、 (90.0±10.3)g/L,随着胎龄和出生体重增加,贫血出现时间延迟,程度减轻(P均<0.05).出生时基础Hb值≤145 g/L的早产儿,贫血出现时间为(7.1±1.4)天,Hb平均值为(100.0±9.2)g/L,与出生时基础Hb值>145 g/L的早产儿比较,贫血时间早(P<0.05).需机械通气者贫血出现时间为(10.5±3.4)天,Hb平均值为(88.7±9.5)g/L,与非机 械通气组比较,贫血出现时间早,程度重(P<0.05).多元线性回归分析显示,胎龄、出生体重和基础Hb值为早产儿贫血出现时间的影响因素,胎龄和基础 Hb值是影响最低Hb值的因素.结论 胎龄越小,出生体重越低,贫血出现时间越早,贫血程度越重.基础Hb值越低,贫血出现越早.需机械通气者因病情重,受多种因素影响可加重早产儿贫血.
[本文引用:1]
[9] AWOGU A U,ABOHWEYERE A E.Alpha erythropoietin in the management of anaemia of prematurity:a report of three cases in Nigeria[J].Niger Postgrad Med J,2006,13(4):361-365.
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[10] MATSUYAMA T,TANAKA T,TATSUMI K,et al.Midazo-lam inhibits the hypoxia-induced up-regulation of erythropoietin in the central nervous system[J].Eur J Pharmacol,2015,76(11):89-98.
Erythropoietin (EPO), a regulator of red blood cell production, is endogenously expressed in the central nervous system. It is mainly produced by astrocytes under hypoxic conditions and has proven to have neuroprotective and neurotrophic effects. In the present study, we investigated the effect of midazolam on EPO expression in primary cultured astrocytes and the mouse brain. Midazolam was administered to 6-week-old BALB/c male mice under hypoxic conditions and pregnant C57BL/6N mice under normoxic conditions. Primary cultured astrocytes were also treated with midazolam under hypoxic conditions. The expression of EPO mRNA in mice brains and cultured astrocytes was studied. In addition, the expression of hypoxia-inducible factor (HIF), known as the main regulator of EPO, was evaluated. Midazolam significantly reduced the hypoxia-induced up-regulation of EPO in BALB/c mice brains and primary cultured astrocytes and suppressed EPO expression in the fetal brain. Midazolam did not affect the total amount of HIF proteins but significantly inhibited the nuclear expression of HIF-1 and HIF-2 proteins. These results demonstrated the suppressive effects of midazolam on the hypoxia-induced up-regulation of EPO both in vivo and in vitro.
DOI:10.1016/j.ejphar.2015.05.024      PMID:26001375      URL    
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[11] YUAN R,WANG B,LU W,et al.A distinct region in erythropoietin that induces immuno/inflammatory modulation and tissue protection[J].Neurotherapeutics,2015,12(4):850-861.
Beneficial effects of short-term whole-molecule erythropoietin (EPO) therapy have been demonstrated on several animal models of diverse central nervous system pathology. However, the increased hematocrit induced by EPO-driven marrow stimulation greatly limits its potential for side effect-free therapy. We created a library of EPO-derived fragments based on the hypothesis that 2 distinct functions, erythropoiesis and tissue protection, reside in different regions of the molecule. Several small EPO-derived peptides within the A loop of whole EPO molecule were screened for tissue protection in EAE mice. The 19-mer JM-4 peptide that contains 2 cysteine molecules consistently demonstrated the most potent clinical beneficial effects without producing hematocrit alterations in animal models of EAE. The JM-4-induced tissue protection was associated with modulation of the immunoregulatory process that drives inflammation and provokes subsequent autoimmune damage. Like the whole EPO molecule, JM-4 effectively modulated immune/inflammatory reaction within both the peripheral lymphatic tissue and central nervous system. The major effects induced by JM-4 include blocked expansion of monocyte/dendritic antigen presenting cell and T helper 17 cell populations, decreased proinflammatory cytokine production, and sharply enhanced expansion of the regulatory T-cell population. JM-4 shows promise for treatment of a broad spectrum of neural and non-neural conditions associated with inflammation.
DOI:10.1007/s13311-015-0379-1      PMID:26271954      URL    
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[12] NAGAYA Y,AOYAMA T,TAMURA T,et al.Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α[J].Eur J Neurosci,2014,40(11):3620-3626.
Abstract Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood–brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo . In cultured astrocytes exposed to hypoxic conditions for 6 and 1202h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response.
DOI:10.1111/ejn.12747      PMID:25283246      URL    
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[13] 董海鹏,宋燕燕,谭美珍,.重组人促红细胞生成素对早产儿脑损伤保护作用的分析[J].中国妇幼健康研究,2016,27(5):568-570,576.
目的探讨重组人促红细胞生成素(rh EPO)对早产儿脑组织的保护作用及其对早产儿纠正年龄1岁内智能发育的影响。方法选择2013年12月至2014年12月广州市妇女儿童医疗中心珠江新城院区新生儿病房收治的出生胎龄34周早产儿为研究对象。其中,经患儿家属知情同意后于住院期间使用rh EPO治疗(生后7天开始,250 IU/kg,皮下注射,每周3次)的治愈出院早产儿101例为促红细胞生成素(EPO)组;患儿家属不同意住院期间使用rh EPO治疗的治愈出院早产儿93例为对照组。比较两组患儿42天时的脑干诱发电位(BAEP)及纠正年龄3~6月龄、9~12月龄时的智能发育情况。结果 1EPO组42例和对照组37例患儿BAEP检查报告进行分析:对照组左耳Ⅲ波、Ⅴ波波峰潜伏期(PL)均明显长于EPO组(t值分别为-2.350、-2.357,均P0.05);对照组右耳Ⅰ波、Ⅲ波、Ⅴ波PL均明显长于EPO组(t值分别为-8.494、-2.063、-2.179,均P0.05);对照组左耳Ⅰ~Ⅲ波、Ⅰ~Ⅴ波波峰间潜伏期(IPL)均明显长于EPO组(t值分别为-2.851、-2.634,均P0.05);2对早产儿纠正年龄3~6月龄时进行Gesell测试:EPO组80例,对照组71例,EPO组大运动、精细运动、语言、个人社交发育商均高于对照组,差异均具有统计学意义(t值分别为-2.658、-5.292、-2.311、-4.169,均P0.05);早产儿纠正年龄9~12个月时参加Gesell测试的早产儿为:EPO组72例,对照组59例,EPO组大运动、语言、适应性、个人社交发育商均高于对照组,差异均具有统计学意义(t值分别为-2.082、-2.355、-2.065、-2.385,均P0.05);3EPO组支气管肺发育不良、颅内出血、BAEP异常发生率明显低于对照组,差异均具有统计学意义(χ2值分别为6.686、4.628、4.366,均P0.05)。结论出生胎龄34周早产儿生后7天开始使用rh EPO治疗可以降低住院期间支气管肺发育不良、颅内出血及脑干听觉诱发电位异常的发生率,有利于促进早产儿纠正胎龄1岁内的智能发育。
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[14] RANGARAJAN V,JUUL S E.Erythropoietin:emerging role oferythropoietin in neonatal neuroprotectionⅢ[J].Pediatr Neurol,2014,51(4):481-488.
In the last two decades, there has been considerable evolution in understanding the role of erythropoietin in neuroprotection. Erythropoietin has both paracrine and autocrine functions in the brain. Erythropoietin binding results in neurogenesis, oligodendrogenesis, and angiogenesis. Erythropoietin and its receptor are upregulated by exposure to hypoxia and proinflammatory cytokines after brain injury. While erythropoietin aids in recovery of locally injured neuronal cells, it provides negative feedback to glial cells in the penumbra, thereby limiting extension of injury. This forms the rationale for use of recombinant erythropoietin and erythropoietin mimetics in neonatal and adult injury models of stroke, traumatic brain injury, spinal cord injury, intracerebral hemorrhage, and neonatal hypoxic ischemia. Review of published literature (Pubmed, Medline, and Google scholar). Preclinical neuroprotective data are reviewed, and the rationale for proceeding to clinical trials is discussed. Results from phase I/II trials are presented, as are updates on ongoing and upcoming clinical trials of erythropoietin neuroprotection in neonatal populations. The scientific rationale and preclinical data for erythropoietin neuroprotection are promising. Phase II and III clinical trials are currently in process to determine the safety and efficacy of neuroprotective dosing of erythropoietin for extreme prematurity and hypoxic-ischemic encephalopathy in neonates.
DOI:10.1016/j.pediatrneurol.2014.06.008      PMID:4180944      URL    
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[15] ROBERTSON C S,YAMAL J M,TILLEY B C.Erythro-poietin for traumatic brain injury-reply[J].JAMA,2014,312(18):1928-1929.
Most of the evidence to date supporting neuroprotection after traumatic brain injury with erythropoietin administration comes from experimental studies. Two case-matched studies in patients with traumatic brain injury and large clinical trials in general trauma patients have found improvements in mortality with erythropoietin treatment.For patients with traumatic brain injury, however, recovery of neurological function long-term is more important than simple survival and none of these previous studies have adequately addressed long-term outcome.
DOI:10.1001/jama.2014.12744      PMID:25387193      URL    
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[16] NICHOL A,LITTLE L,FRENCH C.Erythro-poietin for traumatic brain injury[J].JAMA,2014,312(18):1928-1929.
Most of the evidence to date supporting neuroprotection after traumatic brain injury with erythropoietin administration comes from experimental studies. Two case-matched studies in patients with traumatic brain injury and large clinical trials in general trauma patients have found improvements in mortality with erythropoietin treatment.For patients with traumatic brain injury, however, recovery of neurological function long-term is more important than simple survival and none of these previous studies have adequately addressed long-term outcome.
DOI:10.1001/jama.2014.12744      PMID:25387193      URL    
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[17] FANG A Y,GONZALEZ F F,SHELDON R A,et al.Effects of combination therapy using hypothermja and erythropoietin in arat model of neonatal hypoxia-ischemia[J].Pediatr Res,2013,73(1):12-17.
BACKGROUND: Hypoxic-ischemic (HI) injury to the developing brain remains a major cause of morbidity. Hypothermia is effective but does not provide complete neuroprotection, prompting a search for adjunctive therapies. Erythropoietin (Epo) has been shown to be beneficial in several models of neonatal HI. This study examines combination hypothermia and treatment with erythropoietin in neonatal rat HI. METHODS: Rats at postnatal day 7 were subjected to HI (Vannucci model) and randomized into four groups: no treatment, hypothermia alone, Epo alone, or hypothermia and Epo. Epo (1,000 U/kg) was administered in three doses: immediately following HI, and 24 h and 1 wk later. Hypothermia consisted of whole-body cooling for 8 h. At 2 and 6 wk following HI, sensorimotor function was assessed via cylinder-rearing test and brain damage by injury scoring. Sham-treated animals not subjected to HI were also studied. RESULTS: Differences between experimental groups, except for Epo treatment on histopathological outcome in males, were not statistically significant, and combined therapy had no adverse effects. CONCLUSION: No significant benefit was observed from treatment with either hypothermia or combination therapy. Future studies may require older animals, a wider range of functional assays, and postinsult assessment of injury severity to identify only moderately damaged animals for targeted therapy.
DOI:10.1038/pr.2012.138      PMID:23085817      URL    
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[18] JUUL S E,PET G C.Erythropoietin and neonatal neuropro-tection[J].Clin Perinalol,2015,42(3):469-481.
DOI:10.1016/j.clp.2015.04.004      URL    
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[19] 傅自力,崔聪明,杨洁,.白细胞介素-6白细胞介素-17白细胞介素-23及转化生长因子-β1在肉芽肿性多血管炎患者血清中的表达[J].中国药物与临床,2018,18(增1):1-3.
目的探讨白细胞介素(IL)-6、IL-17、IL-23及转化生长因子(TGF)-β1与肉芽肿性多血管炎(GPA)活动度的关系,明确影响GPA病情变化的机制。方法选取10例病情活动的GPA患者作为研究对象并给予治疗,采用酶联免疫吸附试验(ELISA)检测患者治疗前后IL-6、IL-17、IL-23、TGF-β1的血清浓度。结果 (1)GPA患者治疗前IL-6、IL-17、IL-23、TGF-β1血清表达水平与治疗后比较差异均有统计学意义(P<0.05)。(2)IL-17、IL-23表达水平与伯明翰血管炎活动指数评分相关(r=0.669,P=0.035;r=0.924,P<0.01),其中,IL-23表达水平与伯明翰评分呈正相关。结论 IL-6、IL-17、IL-23、TGF-β1均参与GPA病情活动过程,且IL-23与GPA病情活动度密切相关。
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[20] WU Y W,GONZALEZ F F.Erythropoietin:a novel therapy for hypoxicischaemic encephalopathy?[J].Dev Med Child Neurol,2015,57(Suppl 3):34-39.
Perinatal hypoxic schaemic encephalopathy (HIE) occurs in 1 to 3 per 1000 term births. HIE is not preventable in most cases, and therapies are limited. Hypothermia improves outcomes and is the current standard of care. Yet, clinical trials suggest that 44 53% of infants who receive hypothermia will die or suffer moderate to severe neurological disability. In this article, we review the preclinical and clinical evidence for erythropoietin (EPO) as a potential novel neuroprotective agent for the treatment of HIE. EPO is a novel neuroprotective agent, with remarkable neuroprotective and neuroregenerative effects in animals. Rodent and primate models of neonatal brain injury support the safety and efficacy of multiple EPO doses for improving histological and functional outcomes after hypoxia-ischaemia. Small clinical trials of EPO in neonates with HIE have also provided evidence supporting safety and preliminary efficacy in humans. There is currently insufficient evidence to support the use of high-dose EPO in newborns with HIE. However, several on-going trials will provide much needed data regarding the safety and efficacy of this potential new therapy when given in conjunction with hypothermia for HIE. Novel neuroprotective therapies are needed to further reduce the rate and severity of neurodevelopmental disabilities resulting from HIE. High-dose EPO is a promising therapy that can be administered in conjunction with hypothermia. However, additional data are needed to determine the safety and efficacy of this adjuvant therapy for HIE.
DOI:10.1111/dmcn.12730      PMID:25800490      URL    
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关键词(key words)
重组人促红细胞生成素
早产儿
贫血
白细胞介素

Recombinant human erythro...
Premature infant
Anemia
Interleukin

作者
何兴宇
边朋
张怡

HE Xingyu
BIAN Peng
ZHANG Yi