Clugston Robin D, Klattig Jürgen, Englert Chistoph, Clagett-Dame Margaret, Martinovic Jelena, Benachi Alexandra, Greer John J
Department of Physiology, University of Alberta, 513 HMRC, Edmonton, AB, Canada, T6G 2S2.
Am J Pathol. 2006 Nov;169(5):1541-9. doi: 10.2353/ajpath.2006.060445.
Congenital diaphragmatic hernia (CDH) is a frequently occurring, major congenital abnormality that has high mortality and significant morbidity in survivors. Currently, the pathogenesis of CDH is poorly understood. In this study, we have compared the anatomical characteristics of diaphragm defects in the well-described nitrofen model with the pathogenesis of CDH in vitamin A-deficient rats and wt1 null-mutant mice, representing teratogen-induced, dietary and genetic models of CDH, respectively. Our histological investigations, aided by three-dimensional reconstruction of the developing diaphragm, revealed a common pathogenic mechanism with regards to the location of the diaphragm defect in the foramen of Bochdalek (posterolateral diaphragm) and specific abnormalities within the primordial diaphragm. Furthermore, our analysis of postmortem specimens highlighted similarities in human cases of CDH and these animal models, supporting our hypothesis that CDH in humans arises from a defect in the primordial diaphragm. Immunohistochemical data were consistent with the defect in the primordial diaphragm being in the nonmuscular component. Importantly, these data show that very distinct models of CDH all share a common pathogenic mechanism and, together with supporting evidence from pathological specimens, highlight our proposed pathogenic model for CDH.
先天性膈疝（CDH）是一种常见的主要先天性异常疾病，死亡率高，幸存者也有明显的发病情况。目前，CDH的发病机制尚不清楚。在本研究中，我们将已充分描述的硝呋烯腙模型中膈肌缺损的解剖特征与维生素A缺乏大鼠和wt1基因敲除小鼠中CDH的发病机制进行了比较，这两种模型分别代表了致畸剂诱导、饮食和基因导致的CDH模型。我们的组织学研究在发育中膈肌的三维重建辅助下，揭示了关于Bochdalek孔（后外侧膈肌）中膈肌缺损位置以及原始膈肌内特定异常情况的共同致病机制。此外，我们对尸检标本的分析突出了人类CDH病例与这些动物模型的相似性，支持了我们关于人类CDH源于原始膈肌缺陷的假设。免疫组织化学数据与原始膈肌缺陷存在于非肌肉成分中的情况一致。重要的是，这些数据表明，非常不同的CDH模型都共享一种共同的致病机制，并且与病理标本的支持证据一起，突出了我们提出的CDH致病模型。
