Lung and liver growth and retinoic acid status in human fetuses with congenital diaphragmatic hernia

• Published in: Early human development Vol. 116; pp. 17 - 23
• Main Authors: Loo, Christine K.C., Pearen, Michael A., Pereira, Tamara N., Perry-Keene, Joanna, Payton, Diane, Ramm, Grant A.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.01.2018
• Subjects: Autopsy; Case-Control Studies; cRBP-1; Diaphragmatic hernia; Female; Gestational Age; Glial Fibrillary Acidic Protein - metabolism; Hepatic Stellate Cells - metabolism; Hernias, Diaphragmatic, Congenital - embryology; Hernias, Diaphragmatic, Congenital - metabolism; Human fetus; Humans; Liver - embryology; Liver growth; Lung - embryology; Lung growth; Male; Organ Size; Pregnancy; Retinol-Binding Proteins, Cellular - metabolism; Tretinoin - metabolism; Diaphragmatic hernia; cRBP-1; Human fetus; Liver growth; Lung growth
• ISSN: 0378-3782; 1872-6232
• DOI: 10.1016/j.earlhumdev.2017.10.005

Abnormal retinoic acid (RA) signalling is considered a major cause of congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia and pulmonary hypertension are the major causes of morbidity and mortality in infants born with CDH. Experimental studies in animals have found that RA signalling is involved in lung and liver development, but animal models of CDH do not directly correlate with CDH in human fetuses. This study investigated if RA status is also linked to lung and liver growth in human fetuses with CDH. Hepatic stellate cells (HSC) in autopsy human fetal liver tissue were identified using cRBP-1 immunohistochemistry and the numbers of HSC manually counted. In mammals, RA is principally stored in HSC complexed to cRBP-1 and therefore cRBP-1+ HSC numbers were used as an indicator of fetal RA status. The number of HSCs was correlated with liver and lung weights, calculated relative to either normal biometric values or fetal body weight. The number of cRBP-1+ HSCs correlated with lung weight contralateral to the side of the diaphragmatic hernia (r=0.82, p=0.025) and combined lung weight (r=0.78, p=0.039) but not with ipsilateral lung weight (r=0.43, p=0.33), in fetuses with right and left CDH and a case of giant omphalocoele. Liver growth was influenced by contact with diaphragm but not significantly correlated with cRBP-1 expression (r=0.52, p=0.056). Fetal RA stores, reflected in the number of cRBP-1+ HSCs, influence lung growth as well as diaphragm development in human fetuses with CDH. Contact with diaphragm influenced liver growth. •Data on retinoic acid abnormalities. a major cause of Congenital Diaphragmatic Hernia, are mostly obtained via animal studies•Lung and liver growth are of special interest but there is limited information from human studies.•We compared retinoic acid levels, lung and liver development in human autopsy fetal tissue with findings from animal studies.•Fetal retinoic acid levels influence lung and liver growth in human fetuses with Congenital Diaphragmatic Hernia.•Liver growth is also influenced by contact with diaphragm.