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先天性膈疝中的早期肺部畸形

Early lung malformations in congenital diaphragmatic hernia.

作者信息

Jesudason E C, Connell M G, Fernig D G, Lloyd D A, Losty P D

机构信息

Department of Paediatric Surgery, Insitute of Child Health, Alder Hey Children's Hospital and The School of Biological Sciences, University of Liverpool, England.

出版信息

J Pediatr Surg. 2000 Jan;35(1):124-7; discussion 128. doi: 10.1016/s0022-3468(00)80028-7.

Abstract

BACKGROUND/PURPOSE: Lung hypoplasia, a leading contributor to the lethality of congenital diaphragmatic hernia (CDH), has been attributed to compression of the fetal lung by herniated abdominal viscera. Contested findings in experimental CDH suggest that lung malformation may precede diaphragmatic hernia. To address this unresolved question, we studied the pattern and progress of embryonic lung development in vivo and in vitro before diaphragmatic herniation in the nitrofen CDH model.

METHODS

Sprague-Dawley rats were fed nitrofen on day 9.5 of pregnancy to induce pulmonary hypoplasia and CDH in newborns (term, day 22). Control rats received olive oil. Embryonic lungs were microdissected on day 13.5 gestation, 24 hours after lung primordia bud from the foregut (normal diaphragmatic closure, day 16.5). In vivo airway branching was measured by counting terminal lung buds at this stage. Lungs were cultured for up to 78 hours and longitudinal in vitro development studied by serial measurements of terminal bud count, area, and perimeter.

RESULTS

At 13.5 days of gestation in vivo, nearly 99% of normal lungs (n = 130) had > or = 6 terminal lung buds. In contrast, 36% of the nitrofen-exposed lungs (n = 170) fell short of this developmental milestone with less than 6 terminal buds (P < .001). In vitro, the nitrofen lungs had reduced area compared with controls after 6, 30, and 54 hours (P = .001, P < .001, and P = .001, respectively). Bud count and epithelial perimeter were reduced in the nitrofen lungs after 6 and 30 hours in vitro (P < .001 and P = .01 v normal terminal bud count; P < .001 and P= .002 v normal perimeter).

CONCLUSIONS

Before diaphragmatic herniation, nitrofen-exposed embryos in vivo have a 36% frequency of reduced airway branching that strikingly parallels the 30% to 40% term incidence of CDH in this model. The authors propose that this early lung anomaly is restricted to a subset of nitrofen-exposed embryos in which it is integral to an emerging CDH phenotype. In vitro data confirm that nitrofen-induced pulmonary hypoplasia precedes visceral herniation and persists to allow experimental manipulation in culture. The developmental biology underlying lung hypoplasia in CDH may now be addressed using this organ culture system.

摘要

背景/目的:肺发育不全是先天性膈疝(CDH)致死的主要原因,一直被认为是疝入的腹腔脏器对胎儿肺产生压迫所致。实验性CDH中存在争议的研究结果表明,肺畸形可能先于膈疝出现。为解决这一尚未解决的问题,我们在体内和体外研究了在硝基芬诱导的CDH模型中膈疝形成前胚胎肺发育的模式和进程。

方法

在妊娠第9.5天给Sprague-Dawley大鼠喂食硝基芬,以诱导新生大鼠(足月,第22天)出现肺发育不全和CDH。对照大鼠给予橄榄油。在妊娠第13.5天,即肺原基从前肠发出24小时后(正常膈关闭时间为第16.5天),对胚胎肺进行显微解剖。在此阶段,通过计数终末肺芽来测量体内气道分支情况。将肺培养长达78小时,并通过连续测量终末芽数量、面积和周长来研究体外纵向发育情况。

结果

在妊娠第13.5天的体内实验中,近99%的正常肺(n = 130)有≥6个终末肺芽。相比之下,暴露于硝基芬的肺中36%(n = 170)未达到这一发育里程碑,终末芽少于6个(P <.001)。在体外,与对照组相比,硝基芬处理的肺在培养6、30和54小时后面积减小(分别为P =.001、P <.001和P =.001)。体外培养6和30小时后,硝基芬处理的肺中芽数量和上皮周长减少(与正常终末芽数量相比P <.001和P = 0.01;与正常周长相比P <.001和P = 0.002)。

结论

在膈疝形成前,体内暴露于硝基芬的胚胎气道分支减少的发生率为36%,这与该模型中CDH足月发病率30%至40%惊人地相似。作者提出,这种早期肺异常仅限于暴露于硝基芬的一部分胚胎,它是新出现的CDH表型的一个组成部分。体外数据证实,硝基芬诱导的肺发育不全先于脏器疝出,并持续存在以便在培养中进行实验操作。现在可以使用这种器官培养系统来研究CDH中肺发育不全的发育生物学基础。

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