Pathogenesis Of Congenital Diaphragmatic Hernia Research Articles

Congenital diaphragmatic hernia—Does the side of the defect influence the incidence of associated malformations?

Background/Purpose: Patients with congenital diaphragmatic hernia (CDH) frequently have associated anomalies. Experiments in the nitrofen CDH model have shown differential embryonic cell death patterns in rodents suggesting unique mechanisms in the formation of right-sided (RCDH) or left-sided (LCDH) diaphragmatic hernia. These findings provide insight into the pathogenesis of CDH and may aid our understanding on the spectrum of associated anomalies commonly observed in humans. This study therefore set out to test the hypothesis that the side of the diaphragmatic defect in humans is related to the incidence and severity of coexistent organ malformations. Methods: The medical and autopsy records of 301 CDH patients presenting to two institutions over a 23-year period were examined to analyze these factors. Results: One hundred patients (33%) were found to have one or more associated anomalies. The incidence of multiple—RCDH (10%) versus LCDH (7.3%) and cardiac anomalies—RCDH (10%) versus LCDH (8.5%) was similar in both groups of patients. However, the hypoplastic heart syndrome was a unique feature in 5 of 22 patients (23%) with LCDH who had cardiac abnormalities. This cardiac anomaly may be related developmentally to LCDH. Conclusion: The cellular mechanisms underlying the genesis of this spectrum of abnormalities in humans and the nitrofen CDH model warrant further study to elucidate factors governing embryonic cell fate and phenotype expression.

Pathogenesis of nitrofen-induced congenital diaphragmatic hernia in fetal rats.

Congenital diaphragmatic hernia (CDH) is a developmental anomaly characterized by the malformation of the diaphragm and impaired lung development. In the present study, we tested several hypotheses regarding the pathogenesis of CDH, including those suggesting that the primary defect is due to abnormal 1) lung development, 2) phrenic nerve formation, 3) developmental processes underlying diaphragmatic myotube formation, 4) pleuroperitoneal canal closure, or 5) formation of the primordial diaphragm within the pleuroperitoneal fold. The 2,4-dichloro-phenyl-p-nitrophenyl ether (nitrofen)-induced CDH rat model was used for this study. The following parameters were compared between normal and herniated fetal rats at various stages of development: 1) weight, protein, and DNA content of lungs; 2) phrenic nerve diameter, axonal number, and motoneuron distribution; 3) formation of the phrenic nerve intramuscular branching pattern and diaphragmatic myotube formation; and 4) formation of the precursor of the diaphragmatic musculature, the pleuroperitoneal fold. We demonstrated that previously proposed theories regarding the primary role of the lung, phrenic nerve, myotube formation, and the closure of pleuroperitoneal canal in the pathogenesis of CDH are incorrect. Rather, the primary defect associated with CDH, at least in the nitrofen rat model, occurs at the earliest stage of diaphragm development, the formation of the pleuroperitoneal fold.

Nitrofen-induced diaphragmatic hernias in rats: An animal model

In embryological terms, pathogenesis of congenital diaphragmatic hernia (CDH) associated with pulmonary hypoplasia is still unclear. However, it is known since 1971 that Nitrofen (2,4-dichloro-phenyl-p-nitrophenyl ether) can induce anatomical malformations in rats including diaphragmatic hernias. On order to establish an animal model of the embryogenesis of CDH, the effect of Nitrofen on the developing diaphragm was studied. Thirty-three pregnant female rats were exposed to Nitrofen. Five unexposed pregnant rats served as controls. In the first set of experiments, single doses of Nitrofen were given between the 9th and 13th day of pregnancy. In the second set of experiments, dosages of 50, 100, and 150 mg per animal were given on day 11 of pregnancy only. Postnatally the litters (469 newborn rats) were dissected to record the incidence of diaphragmatic malformations. The results were: (1) most hernias occurred after administration of 100 mg Nitrofen on day 9 (42%) and 11 (59%); (2) left-sided hernias were observed only after exposure to Nitrofen on day 9; (3) after exposure on day 10 or later all hernias were on the right side; and (4) Fifty-nine percent of the newborn rats exposed on day 11 had CDH. These results show that this model is suitable for further embryological investigations on the development of CDH.

Pathophysiology of congenital diaphragmatic hernia: I. Renal enlargement suggests feedback modulation by pulmonary derived renotropins — A unifying hypothesis to explain pulmonary hypoplasia, polyhydramnios, and renal enlargement in the fetus/newborn with congenital diaphragmatic hernia

Survival of newborns with congenital diaphragmatic hernia (CDH) is largely dependent on the severity of pulmonary hypoplasia (PH) present at birth. Intrathoracic compression by the herniated abdominal viscera is thought to be the primary factor involved in the pathogenesis of the PH in CDH. Humoral and/or amniotic pulmonary growth factors (PGF) have been hypothesized to play a role in normal fetal pulmonary development and may be involved in the pathogenesis of CDH as well. The hypothesis of this paper is that growth of the fetal lung is stimulated by a PGF produced by the kidneys, which is modulated by a feedback signal from the lungs, a pulmonary derived renotropin (PDR). In the fetus with CDH, the lungs may be unable to respond to PGF due to compression by the herniated abdominal viscera. Theoretically, PH associated with CDH would maximally stimulate this feedback loop to release more PDR, resulting in continual stimulation of the kidneys and renal enlargement. If such a schema plays a role in the in utero pathophysiology of CDH, then newborns with CDH should have enlarged kidneys. To investigate this hypothesis, we reviewed 30 autopsy cases of newborns with CDH and analyzed their kidney weights versus body weights, using historical data as a control. Kidney weights in CDH cases were greater than the control population in 77% of the cases; 57% of kidney weights were more than one standard deviation above control values. Adjusted group mean kidney weights were 29.8 g (±1.0 SE) in CDH cases and 25.9 g (±1.5 SE) in the control population ( P < .04). These data support our hypothesis and demonstrate that in newborns with CDH and morphologically normal kidneys, there is significant renal enlargement associated with CDH. The presumed mechanism of this renal enlargement, as well as its relationship to normal and aberrant pulmonary growth and regulation are discussed. If such a selective PGF exists, its therapeutic implications for fetuses and newborns with PH are considerable.