2015, Vol. 17
先天性膈疝(congenital diaphragmatic hernia,CDH)是因一侧或双侧膈肌发育缺陷,导致腹腔器官进入胸腔,而引起系列病理生理变化的先天性疾病。其发病率约为1:2 200[1],随着各种治疗技术的发展,CDH病死率下降,但仍高达35%[2]。CDH患儿生后主要临床表现与肺发育不良(pulmonary hyperplasia,PH)和新生儿持续性肺动脉高血压(persistent pulmonary hypertension of the newborn,PPHN)有关。CDH不仅是外科急症,也是引起呼吸、心脏衰竭的病理生理急症,出生后加强监护并积极治疗可提高存活率[3]。CDH继发PPHN (后文称CDH-PPHN)病因不明,国内外相关研究尚无统一结论,出生后缺乏有效治疗,所以阻断CDH形成过程的产前干预技术已成研究热点,现做如下综述。
1 CDH-PPHN病理与病理生理患儿的肺部病理检查发现:肺泡周围毛细血管减少(肺血管床减少)和肺中小动脉中膜增厚(血管平滑肌细胞增多)、大动脉变性等,即PPHN表现;也发现肺泡数量和支气管分支减少、单个肺泡腔容积增大、肺泡间隔增厚等肺发育不良表现[4, 5]。Acker等[6]通过对9例CDH死亡患儿肺部组织学研究发现:在低肺泡化的肺组织中,由于肺内血管与支气管动脉的异常吻合,导致支气管-肺的异常血液分流而引起难治性低氧血症。CDHPPHN以高肺动脉压和高右心压力而引起患儿心脏血液右向左分流为特点[7]。右心压力高,血液通过未闭的卵圆孔和动脉导管自右向左分流,造成低氧血症、二氧化碳潴留和代谢性酸中毒。低氧又引起肺血管痉挛收缩,进一步增加肺血管阻力而加重右向左分流,以上恶性循环最终导致循环、呼吸衰竭而增加病死率。
2 CDH-PPHN发病机制研究进展CDH肺血管发育畸形与PH的关系密不可分,可能相互影响(肺血管与支气管在分支出芽时可能互为模板,具体机制不明),PH也可能引起肺血管的畸形,CDH中肺血管畸形是由支气管畸形引起的还是原发性的,尚不清楚。PH的病因并不明确,目前在CDH肺内观察到基因(如:TTF-1、Fog-2、GATA-6等)、细胞因子(如:EGF、TNF-α、FGF等)、肺表面活性物质、离子通道等的变化[8],这提示PH为多因素致病。Keijzer等[9]提出的"双重打击"学说认为CDH时的肺被疝入胸腔的组织器官机械压迫,也受到遗传/环境等未知因素的影响,两重因素的影响导致PH。CDH-PPHN的病因也不明确,有较多影响因素。形态上,CDH肺表现为肺血管床减少与肺中小动脉中膜层增厚,管腔狭窄,前者与内皮细胞的增殖、迁移功能相关,后者与肺动脉血管平滑肌细胞(pulmonary artery smooth muscle cells,PASMCs)增殖增强、凋亡减弱有关[10]。功能上,CDH肺动脉对舒肺动脉药物反应性差,进一步研究发现:肺中小动脉舒缩调节系统受损[11]。综上,CDH时肺血管的异常表现为血管内皮与血管平滑肌细胞的异常。
2.1 血管内皮细胞的增殖异常CDH时肺血管床减少,血管发育与血管内皮细胞的增殖、出芽、迁移等功能密切相关,这提示血管内皮细胞的增殖功能受损。Acker等[12]通过膈疝山羊模型的肺血管内皮细胞发现:CDH组血管内皮细胞的高增殖压型(highly proliferative population of pulmonary artery endothelial cell,HPPAEC)明显减少,增殖能力、形成管状的能力下降,由此推测CDH的肺血管低增殖性与异常的血管内皮细胞表型分布有关。
除此之外,血管内皮细胞的增殖功能还与其正负调控因子有关。多项研究证实[13]血管内皮生长因子A (vascular endothelial growth factor A,VEGF-A)及其受体(VEGFR2)具有促进血管内皮细胞出芽、分枝、迁移功能。Sbragia等[14]发现除草醚诱导的胎鼠CDH模型VEGF受体表达降低。Chang等[15]利用分子生物学检测发现除草醚诱导的胎鼠CDH模型肺中VEGF表达下调。有研究还发现[16],血管发育中Notch1、4受体、DLL4、Jagged1配体等因素也参与血管内皮出芽分支的调控。
2.2 肺动脉血管内皮细胞分泌与舒缩调节异常血管内皮细胞是调节血管舒缩功能的重要细胞,通过血管收缩因子内皮素(ET,主要为ET-1)和血管舒张因子一氧化氮(NO)发挥功能。CDH时ET信号作用增强,而NO信号作用降低。
ET信号作用增强:研究发现在CDH患儿与动物模型肺中ET-1表达增加[17]。ET-1分别激活两种受体后出现相反作用,ET-A (位于PASMCs上)引起血管收缩,ET-B (位于EC上)引起血管舒张[18]。CDH中ET-A、B均表达增加,由于两种受体介导相反作用,CDH肺动脉高压中何种受体起主要作用并不明确[19]。另有研究发现在CDH肺血管中5-羟色胺受体2A (5-HT2A)异常升高,5-HT2A是重要血管收缩因子,并且可促进血管平滑肌细胞增殖[20]。
NO信号作用减弱:NO是体内一种重要的血管舒张因子,作用于PASMCs舒张血管。研究证实[21],NO通过鸟苷酸环化酶(guanylate cyclase,GC)与磷酸二脂酶(phosphodiesterase-5,PDE5)介导血管舒张,激动对照组与CDH组的酶能引起血管舒张,但CDH组效应更弱,由此可知CDH肺中NO信号通路受损,信号减弱。一氧化氮合酶(NOS)是NO合成的限速酶,有三种亚型:eNOS、iNOS、nNOS,eNOS定位于EC。关于eNOS在CDH中的变化,部分研究相互矛盾,Acker等[12]发现CDH中EC表型发生改变,eNOS表达减少,NO合成减少。但Hofmann等[22]发现,eNOS的负调控因子小窝蛋白1(caveolin-1,Cav-1)在CDH肺中表达降低导致eNOS表达增高。因此,在CDH中肺血管NO信号通路受损,但其详细机制并不明确。
2.3 肺动脉平滑肌细胞增殖异常CDH-PPHN时PASMCs表现为增殖与凋亡平衡失调。Hofmann等[10]研究发现,CDH肺血管中Kruppel样因子5(KLF5)及生存素P的基因与蛋白表达增加,KLF5是细胞分化与胚胎发育中具有多种功能的转录因子,其优先表达于增殖的血管平滑肌细胞中,而在分化的细胞中表达减少,这提示KLF5与生存素P的表达增加是CDH-PPHN产生的重要原因。其另一项研究证实[23],CDH模型中肺血管信号传导和转录激活因子3(pSTAT3)和PIM-1表达增加,pSTAT3促进PIM-1的表达,PIM-1可以促进PASMCs的增殖,阻止其凋亡,同时还具有收缩血管作用。
PASMCs有收缩(成熟)与合成(未成熟)两种表型,其增殖能力不同,合成表型增殖能力强,收缩能力差,收缩表型相反[24]。Li等[25]发现肺动脉高压时Notch3信号通路增强同时PASMCs由成熟表型(收缩表型)转换为未成熟表型(合成表型)。但Sluiter等[26]在对不同发育阶段的CDH患者肺组织中发现PASMCs表现为过早成熟(收缩表型增多),关于PASMCs的表型变化,还需进一步研究。
PASMCs增殖、分化受多种因素影响。骨形态发生蛋白-2(BMP-2)信号通路可降低PASMCs对生长因子的敏感性并促进其凋亡而保持增殖与凋亡平衡,是重要的平滑肌细胞增殖负调节通路,过氧化物酶体增殖物激活受体(PPARγ)是BMP-2信号通路的下游信号,BMP-2增强,PPARγ增强[27]。多项研究证实CDH肺中PASMCs负调控因子BMP-2、PPARγ信号通路信号减弱[28, 29, 30]。Hofmann等[31]的研究证实,CDH肺血管中晚期糖基化终末产物受体(RAGE)表达上调,而RAGE是BMP/PPARγ通路上游的负调控因子;其另一项研究发现BMP-2目的基因Apelin的表达,也可抑制PASMCs的增殖,促进其凋亡[32]。以上变化可能提示BMP-2信号通路的抗增殖作用减弱是导致PASMCs过度增殖的原因之一。此外Acker等[33]从血管内皮细胞与血管平滑肌细胞相互作用的角度研究发现:CDH肺中血管内皮细胞的功能障碍,促进了血管平滑肌细胞的增殖,这可能使ET-1增加,ET-1可介导增加内皮细胞合成超氧化物歧化酶,超氧化物歧化酶可促进PASMCs的增殖。
2.4 肺动脉平滑肌细胞的收缩力改变Takayasu等[34]的研究发现:CDH肺血管中Rho激酶A (RhoA)表达增高,RhoA是一种强烈血管收缩因子,具有小GTP酶活性,还发现RhoA具有促进血管平滑肌细胞增殖的作用,应用RhoA阻滞剂法舒地尔后,上述表现受到抑制。
PASMCs表面存在K+、Ca2+离子通道,其调控胞周与胞内的K+、Ca2+离子浓度是调节血管平滑肌张力的重要方式。CDH时肺中离子通道发生变化,Sakai等[35]发现CDH中肺动脉平滑肌细胞膜电压控制K+离子通道(Kv Channal)的表达与功能下降,Kv的活动不仅调节膜电位还调节细胞质内的游离Ca2+浓度。Kv活动降低使PASMCs容易去极化而增加血管张力,增加肺动脉压。Kv活动增加,使电压依赖Ca2+通道阈值降低而增加胞内Ca2+浓度而刺激PASMCs收缩。此外,有研究还发现ATP依赖的K+离子通道(KATP)与在CDH中Kv具有相似的作用[36]。Yamamura等[37]发现在特发性肺动脉高压肺中Ca2+敏感型受体(CaSR)表达增加而导致PASMCs胞内Ca2+浓度增加,其促进肺动脉收缩增加肺动脉压,还刺激PASMCs增殖,同时发现CaSR阻滞剂可以抑制上述生理功能。
3 CDH-PPHN的治疗进展CDH的治疗原则:产前促进肺与血管发育;产后维持呼吸-循环稳定(循环支持,呼吸支持,降低肺动脉压),为手术修补创造条件。
3.1 产前肺动脉高压预测与评估部分CDH患儿生后表现为温和缓慢的发病过程,而有的患儿则表现为明显的严重的肺动脉高压与PH。因此,于产前检出生后高风险的严重肺动脉高压CDH患儿,对生后的针对性治疗、提高存活率有积极意义。产前用超声测量胎儿肝脏位置、胃的位置、肺头比(LHR),胎儿超声心动图测量动脉导管分流量、室间隔位置、三尖瓣反流速率等可评估CDH患儿的肺动脉高压的严重程度[38]。Fleck等[39]在产前胎儿超声诊断CDHPPHN的情况下,检测母血与脐带血中的生物活性物质的变化发现:胎儿产生的生长因子和炎性介质与其肺动脉高压相关,脐带血中发现表皮生长因子(EGF)、血小板性生长因子AA (PDGF-AA)增多,炎性介质干扰素α(IFN-α)、白细胞介素1(IL-1)、白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)等均升高,这些细胞因子均与PPHN相关。Brindle等[40]则研究产后PPHN高风险因素时发现:低体重、Apgar评分小于5分、有染色体或心脏畸形、超声下的肺动脉高压证据是CDH患儿出现肺动脉高压的高危因素。此外CDH患儿血浆脑钠肽(BNP)和VEGF-A增多,胎盘源性生长因子(PLGF)减少与肺动脉高压关系密切[41, 42]。
3.2 产前干预进展(促进肺血管发育)(1)产前应用激素治疗可促进肺发育:前期研究发现,产前用糖皮质激素干预可促进CDH模型动物的胎肺发育,促进肺血管发育,增加肺血管床、降低肺中小动脉壁厚度。Gonçalves等[43]通过对Nitrofen介导的胎鼠CDH模型分别用产前激素(Dex)治疗,生后机械通气治疗,以用生理盐水为对照,监测指标包括肺体重比(TLW/BW)、肺泡前阻力血管中膜平均厚度(MWT)、VEGF、VEGFR1/2、NOS等。发现Dex干预后TLW/BW明显增加、MWT较膈疝组变薄接近对照组,eNOS表达增加、VEGFR2(血管发育负性调控)降低、VEGF降低。但产前应用激素有增加早产的风险,并可增加感染,使胎儿肾上腺功能轻度受抑而限制了其临床应用。
(2)汉防己甲素(tetrandrine,TET):TET是一种从防己科植物粉防己根中提取的生物碱,其药理作用广泛,具有调节血管舒缩、抗纤维化、抗氧自由基、抗炎等生物学效应。肺发育早期给予TET产前干预可使CDH胎鼠肺泡面积增大,肺间隔厚度减小而改善肺组织发育;同时还增加腺泡前血管数量和减小血管壁厚度而缓解患儿生后肺动脉高压[44]。Lin等[45]研究发现CDH中TET能够改善肺血管重构,降低ET-1表达从而改善PPHN。
(3)胎儿镜气管阻塞(Fetoscopic tracheal occlusion,FETO):FETO来源于临床发现:气管闭锁的患儿,往往伴随有其肺组织的过度发育。在肺严重发育不良CDH胎儿早期行气管阻塞能明显增加肺尺寸和肺血管量,从而增加存活率[46]。Ruano等[47]在CDH患儿身上行FETO发现:患儿患侧肺容量比、肺血管化指数均增加,这提示FETO能促进肺发育,促进肺血管发育,从而提高患儿生后存活率。但宫内操作容易引发感染、流产等。
(4)其他产前干预方法:研究者也发现,磷酸二酯酶-5(PDE-5)抑制剂,西地那非能促进CDH肺血管发育,抑制肺平滑肌细胞的过度生长,还能使肺血管中的eNOS恢复正常[48, 49]。此外,在产前药物干预研究中发现:维甲酸、辛伐他汀、伊马替尼等均对降低CDH患儿的肺动脉压具有积极影响[50, 51, 52],但还需进一步研究其安全性和有效性。
3.3 产后治疗进展(1)一般治疗:纠正电解质、酸碱平衡紊乱、缺氧等全身危急状态。
(2)呼吸/循环支持:为改善患儿呼吸循环功能的主要措施有吸氧、机械通气等。机械通气可使CDH肺动脉舒张,同时调节肺内NOS和VEGF信号通路,进而降低肺动脉压[53]。CDH患儿的机械通气策略有其特殊性,主流的通气模式为Wung等[54]描述的温和通气策略+允许高碳酸血症:气压峰值2~5 cm H2O,导管前氧饱和度85%~95%,导管后氧饱和度>70%,PaCO2限制在45~28 mm Hg之间,呼吸末正压应当<28 cm H2O。为保护肺部不受气压伤,低气道压力峰值和轻微的高碳酸血症已逐渐被接受,因此多数医疗中心将高频振荡通气作为前者无效时的备用方案[55]。
(3)呼吸替代:出生后24 h新生儿急性生理学评分-II (SNAP-II)低与高碳酸血症,需要体外膜肺氧合(extracorporeal membrane oxygenation,ECMO)作为补救性治疗[56]。ECMO的使用指征:①导管前氧饱和度<80%,尽管通气压力峰值超过28 cm H2O;②所有治疗无法纠正PPHN或心力衰竭;③孕期>34周;④出生时体重<2 kg[57]。ECMO是通过V-V转流(股静脉引出,颈内静脉泵入)暂时替代肺的换气功能而使肺得到休息,使CDH患儿呼吸、循环功能稳定,在此期间新生儿发育不全的肺得到进一步成熟,可为手术修补膈肌缺损创造良好条件。但ECMO的并发症较严重(主要为出血),在带机状态下行膈疝修补将增加出血风险,建议ECMO呼吸稳定脱机后再行手术,以减少出血风险[58]。
(4)降肺动脉压治疗:iNO治疗是选择性舒张肺动脉,而不造成全身低血压。其应用较普遍,早期iNO治疗可明显提高CDH患儿的氧分压[59]。磷酸二酯酶抑制剂西地那非是一种有效的降肺动脉压药,用于产后CDH-PPHN患儿具有明显的舒张肺动脉压作用[60]。
综上,PPHN是CDH患儿致死的重要原因,治疗棘手,病情危重,生后治疗效果差。病理检查发现肺血管床减少与中小动脉中膜平滑肌层增厚。研究发现,CDH肺动脉高压主要表现为:肺动脉内皮细胞功能障碍,肺动脉平滑肌细胞增殖功能增强、凋亡功能降低,这最终导致了肺动脉高压。CDH患儿出生后治疗方案多,以纠正电解质酸碱紊乱、低血压、缺氧等全身危急状态的一般治疗,降肺动脉压和呼吸支持的特殊治疗为主,但目前产后治疗的效果并不理想,病死率较高。所以若能在产前给予治疗,促进肺血管发育,降低肺动脉压,可降低病死率。但目前CDH-PPHN病因不明,难以开发出针对其病因的产前干预技术,故明确CDH的病因机制有利于产前的靶向治疗,从而找到孕前、产前药物干预突破口,而从根本上预防这一高致死性人类疾病。
| [1] | Hedrick HL. Management of prenatally diagnosed congenital diaphragmatic hernia[J]. Semin Pediatr Surg, 2013, 22(1):37-43. |
| [2] | Mychaliska G, Bryner B, Dechert R, et al. Safety and efficacy of perflubron-induced lung growth in neonates with congenital diaphragmatic hernia:results of a prospective randomized trial[J]. J Pediatr Surg, 2015, 50(7):1083-1087. |
| [3] | Rollins MD. Recent advances in the management of congenital diaphragmatic hernia[J]. Curr Opin Pediatr, 2012, 24(3):379-385. |
| [4] | Cabral JE, Belik J. Persistent pulmonary hypertension of the newborn:recent advances in pathophysiology and treatment[J]. J Pediatr (Rio J), 2013, 89(3):226-242. |
| [5] | Healy F, Lin W, Feng R, et al. An association between pulmonary hypertension and impaired lung function in infants with congenital diaphragmatic hernia[J]. Pediatr Pulmonol, 2014. [Epub ahead of print]. |
| [6] | Acker SN, Mandell EW, Sims-Lucas S, et al. Histologic identification of prominent intrapulmonary anastomotic vessels in severe congenital diaphragmatic hernia[J]. J Pediatr, 2015, 166(1):178-183. |
| [7] | Storme L, Aubry E, Rakza T, et al. Pathophysiology of persistent pulmonary hypertension of the newborn:impact of the perinatal environment[J]. Arch Cardiovasc Dis, 2013, 106(3):169-177. |
| [8] | 吉毅, 刘文英. 先天性膈疝肺发育不良的研究进展[J]. 中国 当代儿科杂志, 2010, 12(4):316-320. |
| [9] | Keijzer R, Liu J, Deimling J, et al. Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia[J]. Am J Pathol, 2000, 156(4):1299-1306. |
| [10] | Hofmann AD, Takahashi T, Duess JW, et al. Increased pulmonary vascular expression of Krüppel-like factor 5 and activated survivin in experimental congenital diaphragmatic hernia[J]. Pediatr Surg Int, 2014, 30(12):1191-1197. |
| [11] | Schmidt AF, Rojas-Moscoso JA, Gonçalves FL, et al. Increased contractility and impaired relaxation of the left pulmonary artery in a rabbit model of congenital diaphragmatic hernia[J]. Pediatr Surg Int, 2013, 29(5):489-494. |
| [12] | Acker SN, Seedorf GJ, Abman SH, et al. Pulmonary artery endothelial cell dysfunction and decreased populations of highly proliferative endothelial cells in experimental congenital diaphragmatic hernia[J]. Am J Physiol Lung Cell Mol Physiol, 2013, 305(12):L943-L952. |
| [13] | Jin Y, Kaluza D, Jakobsson L. VEGF, Notch and TGFβ/BMPs in regulation of sprouting angiogenesis and vascular patterning[J]. Biochem Soc Trans, 2014, 42(6):1576-1583. |
| [14] | Sbragia L, Nassr AC, Gonçalves FL, et al. VEGF receptor expression decreases during lung development in congenital diaphragmatic hernia induced by nitrofen[J]. Braz J Med Biol Res, 2014, 47(2):171-178. |
| [15] | Chang R, Andreoli S, Ng YS, et al. VEGF expression is downregulated in nitrofen-induced congenital diaphragmatic hernia[J]. J Pediatr Surg, 2004, 39(6):825-828. |
| [16] | Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis[J]. Nat Rev Mol Cell Biol, 2007, 8(6):464-478. |
| [17] | Okazaki T, Sharma HS, McCune SK, et al. Pulmonary vascular balance in congenital diaphragmatic hernia:enhanced endothelin-1 gene expression as a possible cause of pulmonary vasoconstriction[J]. J Pediatr Surg, 1998, 33(1):81-84. |
| [18] | Mesdag V, Andrieux J, Coulon C, et al. Pathogenesis of congenital diaphragmatic hernia:additional clues regarding the involvement of the endothelin system[J]. Am J Med Genet A, 2014, 164A(1):208-212. |
| [19] | Dingemann J, Doi T, Ruttenstock E, et al. Upregulation of endothelin receptors A and B in the nitrofen induced hypoplastic lung occurs early in gestation[J]. Pediatr Surg Int, 2010 Jan, 26(1):65-69. |
| [20] | Hofmann AD, Friedmacher F, Hunziker M, et al. Upregulation of serotonin-receptor-2a and serotonin transporter expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia[J]. J Pediatr Surg, 2014, 49(6):871-874. |
| [21] | de Buys Roessingh A, Fouquet V, Aigrain Y, et al. Nitric oxide activity through guanylate cyclase and phosphodiesterase modulation is impaired in fetal lambs with congenital diaphragmatic hernia[J]. J Pediatr Surg, 2011, 46(8):1516-1522. |
| [22] | Hofmann A, Gosemann JH, Takahashi T, et al. Imbalance of caveolin-1 and eNOS expression in the pulmonary vasculature of experimental diaphragmatic hernia[J]. Birth Defects Res B Dev Reprod Toxicol, 2014, 101(4):341-346. |
| [23] | Hofmann AD, Takahashi T, Duess J, et al. Increased expression of activated pSTAT3 and PIM-1 in the pulmonary vasculature of experimental congenital diaphragmatic hernia[J]. J Pediatr Surg, 2015, 50(6):908-911. |
| [24] | Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease[J]. Physiol Rev, 2004, 84(3):767-801. |
| [25] | Li X, Zhang X, Leathers R, et al. Notch3 signaling promotes the development of pulmonary arterial hypertension[J]. Nat Med, 2009, 15(11):1289-1297. |
| [26] | Sluiter I, van der Horst I, van der Voorn P, et al. Premature differentiation of vascular smooth muscle cells in human congenital diaphragmatic hernia[J]. Exp Mol Pathol, 2013, 94(1):195-202. |
| [27] | Hansmann G, de Jesus Perez VA, Alastalo TP, et al. An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension[J]. J Clin Invest, 2008, 118(5):1846-1857. |
| [28] | Makanga M, Dewachter C, Maruyama H, et al. Downregulated bone morphogenetic protein signaling in nitrofen-induced congenital diaphragmatic hernia[J]. Pediatr Surg Int, 2013, 29(8):823-834. |
| [29] | Gosemann JH, Friedmacher F, Fujiwara N, et al. Disruption of the bone morphogenetic protein receptor 2 pathway in nitrofeninduced congenital diaphragmatic hernia[J]. Birth Defects Res B Dev Reprod Toxicol, 2013, 98(4):304-309. |
| [30] | Gosemann JH, Friedmacher F, Hunziker M, et al. Increased activation of NADPH oxidase 4 in the pulmonary vasculature in experimental diaphragmatic hernia[J]. Pediatr Surg Int, 2013, 29(1):3-8. |
| [31] | Hofmann AD, Friedmacher F, Takahashi T, et al. Increased pulmonary vascular expression of receptor for advanced glycation end products (RAGE) in experimental congenital diaphragmatic hernia[J]. J Pediatr Surg, 2015, 50(5):746-749. |
| [32] | Hofmann AD, Friedmacher F, Takahashi H, et al. Decreased apelin and apelin-receptor expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia[J]. Pediatr Surg Int, 2014, 30(2):197-203. |
| [33] | Acker SN, Seedorf GJ, Abman SH, et al. Altered pulmonary artery endothelial-smooth muscle cell interactions in experimental congenital diaphragmatic hernia[J]. Pediatr Res, 2015, 77(4):511-519. |
| [34] | Takayasu H, Masumoto K, Hagiwara K, et al. Increased pulmonary RhoA expression in the nitrofen-induced congenital diaphragmatic hernia rat model[J]. J Pediatr Surg, 2015. [Epub ahead of print]. |
| [35] | Sakai M, Unemoto K, Solari V, et al. Decreased expression of voltage-gated K+ channels in pulmonary artery smooth muscles cells in nitrofen-induced congenital diaphragmatic hernia in rats[J]. Pediatr Surg Int, 2004, 20(3):192-196. |
| [36] | de Buys Roessingh AS, de Lagausie P, Barbet JP, et al. Role of ATP-dependent potassium channels in pulmonary vascular tone of fetal lambs with congenital diaphragmatic hernia[J]. Pediatr Res, 2006, 60(5):537-542. |
| [37] | Yamamura A. Pathological function of Ca2+-sensing receptor in pulmonary arterial hypertension[J]. J Smooth Muscle Res, 2014, 50:8-17. |
| [38] | Lusk LA, Wai KC, Mood-Grady AJ, et al. Fetal ultrasound markers of severity predict resolution of pulmonary hypertension in congenital diaphragmatic hernia[J]. Am J Obstet Gynecol, 2015. [Epub ahead of print]. |
| [39] | Fleck S, Bautista G, Keating SM, et al. Fetal production of growth factors and inflammatory mediators predicts pulmonary hypertension in congenital diaphragmatic hernia[J]. Pediatr Res, 2013, 74(3):290-298. |
| [40] | Brindle ME, Cook EF, Tibboel D, et al. A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns[J]. Pediatrics, 2014, 134(2):e413-e419. |
| [41] | Partridge EA, Hanna BD, Rintoul NE, et al. Brain-type natriuretic peptide levels correlate with pulmonary hypertension and requirement for extracorporeal membrane oxygenation in congenital diaphragmatic hernia[J]. J Pediatr Surg, 2015, 50(2):263-266. |
| [42] | Patel N, Moenkemeyer F, Germano S, et al. Plasma vascular endothelial growth factor A and placental growth factor:novel biomarkers of pulmonary hypertension in congenital diaphragmatic hernia[J]. Am J Physiol Lung Cell Mol Physiol, 2015, 308(4):L378-L383. |
| [43] | Gonçalves FL, Figueira RL, Simoes AL, et al. Effect of corticosteroids and lung ventilation in the VEGF and NO pathways in congenital diaphragmatic hernia in rats[J]. Pediatr Surg Int, 2014, 30(12):1207-1215. |
| [44] | Liu W, Feng J, Jia H, et al. Effect of prenatal tetrandrine therapy on pulmonary vascular structural remodeling in the nitrofeninduced CDH rat model[J]. Chin Med J (Engl), 2000, 113(9):813-816. |
| [45] | Lin H, Wang Y, Xiong Z, et al. Effect of antenatal tetrandrine administration on endothelin-1 and epidermal growth factor levels in the lungs of rats with experimental diaphragmatic hernia[J]. J Pediatr Surg, 2007, 42(10):1644-1651. |
| [46] | Ruano R, Peiro JL, da Silva MM, et al. Early fetoscopic tracheal occlusion for extremely severe pulmonary hypoplasia in isolated congenital diaphragmatic hernia:preliminary results[J]. Ultrasound Obstet Gynecol, 2013, 42(1):70-76. |
| [47] | Ruano R, da Silva MM, Campos JA, et al. Fetal pulmonary response after fetoscopic tracheal occlusion for severe isolated congenital diaphragmatic hernia[J]. Obstet Gynecol, 2012, 119(1):93-101. |
| [48] | Lemus-Varela Mde L, Soliz A, Gomez-Meda BC, et al. Antenatal use of bosentan and/or sildenafil attenuates pulmonary features in rats with congenital diaphragmatic hernia[J]. World J Pediatr, 2014, 10(4):354-359. |
| [49] | Shue EH, Schecter SC, Gong W, et al. Antenatal maternallyadministered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia[J]. J Pediatr Surg, 2014, 49(1):39-45. |
| [50] | Schmidt AF, Gonçalves FL, Regis AC, et al. Prenatal retinoic acid improves lung vascularization and VEGF expression in CDH rat[J]. Am J Obstet Gynecol, 2012, 207(1):76.e25-e32. |
| [51] | Makanga M, Maruyama H, Dewachter C, et al. Prevention of pulmonary hypoplasia and pulmonary vascular remodeling by antenatal simvastatin treatment in nitrofen-induced congenital diaphragmatic hernia[J]. Am J Physiol Lung Cell Mol Physiol, 2015, 308(7):L672-L682. |
| [52] | Chang YT, Ringman Uggla A, Osterholm C, et al. Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia[J]. Am J Physiol Lung Cell Mol Physiol, 2012, 302(11):L1159-L1166. |
| [53] | Gallindo RM, Gonçalves FL, Figueira RL, et al. Ventilation causes pulmonary vascular dilation and modulates the NOS and VEGF pathway on newborn rats with CDH[J]. J Pediatr Surg, 2015, 50(5):842-848. |
| [54] | Wung JT, Sahni R, Moffitt ST, et al. Congenital diaphragmatic hernia:survival treated with very delayed surgery, spontaneous respiration, and no chest tube[J]. J Pediatr Surg, 1995, 30(3):406-409. |
| [55] | Garcia A, Stolar CJ. Congenital diaphragmatic hernia and protective ventilation strategies in pediatric surgery[J]. Surg Clin North Am, 2012, 92(3):659-668. |
| [56] | Coleman AJ, Brozanski B, Mahmood B, et al. First 24-h SNAPII score and highest PaCO2 predict the need for ECMO in congenital diaphragmatic hernia[J]. J Pediatr Surg, 2013, 48(11):2214-2218. |
| [57] | Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO:focus on PPHN[J]. Semin Perinatol, 2005, 29(1):8-14. |
| [58] | Partridge EA, Peranteau WH, Rintoul NE, et al. Timing of repair of congenital diaphragmatic hernia in patients supported by extracorporeal membrane oxygenation (ECMO)[J]. J Pediatr Surg, 2015, 50(2):260-262. |
| [59] | Campbell BT, Herbst KW, Briden KE, et al. Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia[J]. Pediatrics, 2014, 134(2):e420-e426. |
| [60] | Rojas-Moscoso JA, Antunes E, Figueira RR, et al. The soluble guanylyl cyclase activator BAY 60-2770 potently relaxes the pulmonary artery on congenital diaphragmatic hernia rabbit model[J]. Pediatr Surg Int, 2014, 30(10):1031-1036. |