Teratogen-Induced, Dietary and Genetic Models of Congenital Diaphragmatic Hernia Share a Common Mechanism of Pathogenesis

Abstract

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.

Gene expression in the developing diaphragm: significance for congenital diaphragmatic hernia

“…In cases of Bochdalek CDH, which is the most frequent presentation of CDH, incomplete formation of the posterolateral diaphragm allows invasion of the abdominal contents into the thoracic cavity, impeding lung development (32,65). The pathogenesis of CDH is poorly understood; however, recent research using different animal models of the disorder is beginning to provide insight into its embryonic origins (13,22,23). Equally, progress is also being made in understanding the etiology of CDH.…”

“…Muscle precursor cells (MPC) that form the complete musculature of the diaphragm first migrate to the PPF, and it is also the target for pioneer axons of the phrenic nerve that provides the diaphragm with its nervous input (10,29). With regard to CDH, abnormal PPF development has been shown to underlie diaphragmatic hernia in nitrofen-treated rats, vitamin A-deficient rats, and Wt1-null mutant mice (6,23). Furthermore, analyses of human CDH postmortem tissue have generated data consistent with primary PPF defects (23).…”

Konjenital diafragmatik herni ve aortik koarktasyon nadir birlikteliğinin prenatal tanısı

“…CDH is occurred due to the defect of the amuscular component of the primordial diaphragm 6 . The defect causes visceral herniation to fetal thorax and may influence the normal development of the lungs, the bronchi and pulmonary arteries to result in potential pulmonary hypoplasia.…”

Genetics of Congenital Diaphragmatic Hernia

“…Genes affecting PPF development are COUP-TFII, FOG2, GATA-4, WT1 and Disp1, expressed in the non-muscular mesenchymal components of the diaphragm (Clugston et al, 2006;Clugston et al, 2008;Kantarci et al, 2010). Disp 1 is expressed in the primordial pleuroperitoneal fold (PPF), in diaphragmatic tissues and in the developing lung mesothelium, epithelium, and mesenchyme (Kantarci et al, 2010).…”

“…Pathological studies have demonstrated defects in the formation of the primordial pleuroperitoneal folds (PPF) in WT1 null mice (Clugston et al, 2006).…”