title: Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?
abstract: Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-β pathway, a key player in lung development and repair. Pulmonary expression of TGF-β signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-β/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-β transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-β/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined.
authors.affiliation: Laboratory of Physiology and Pathophysiology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium; avuckovi@ulb.ac.be.
authors.forename: Aline
authors.initials: A
authors.lastname: Vuckovic
authors.affiliation: Division of Neonatology, University Children's Hospital, Perinatal Center, Ludwig-Maximilian-University Munich, Munich, Germany;
authors.forename: Susanne
authors.initials: S
authors.lastname: Herber-Jonat
authors.affiliation: Division of Neonatology, University Children's Hospital, Perinatal Center, Ludwig-Maximilian-University Munich, Munich, Germany;
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Flemmer
authors.affiliation: Division of Neonatology, University Children's Hospital, Perinatal Center, Ludwig-Maximilian-University Munich, Munich, Germany;
authors.forename: Ina M
authors.initials: IM
authors.lastname: Ruehl
authors.affiliation: Department of Obstetrics and Gynecology, Fetal Medicine Unit, University Hospital Brugmann, Université Libre de Bruxelles, Brussels, Belgium;
authors.forename: Carmela
authors.initials: C
authors.lastname: Votino
authors.affiliation: Unit of Pediatric Pathology, Pathology Department, University Hospital Brugmann, Université Libre de Bruxelles, Brussels, Belgium;
authors.forename: Valérie
authors.initials: V
authors.lastname: Segers
authors.affiliation: Department of Obstetrics and Gynecology and Centre de Maladie Rare: Hernie de Coupole Diaphragmatique, Hôpital Antoine Béclère, Assistance Publique Hôpitaux de Paris (APHP), Université Paris Sud, Paris, France;
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benachi
authors.affiliation: Unit of Fetal Pathology, Hôpital Antoine Béclère, Assistance Publique Hôpitaux de Paris (APHP), Université Paris Sud, Paris, France;
authors.forename: Jelena
authors.initials: J
authors.lastname: Martinovic
authors.affiliation: Department of Fetal-Maternal Medicine and Gynecology, Medical University and the Research Institute Polish Mother's Memorial Hospital, Lodz, Poland; and.
authors.forename: Dorota
authors.initials: D
authors.lastname: Nowakowska
authors.affiliation: Department of Clinical Pathology, Medical University and the Research Institute Polish Mother's Memorial Hospital, Lodz, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Dzieniecka
authors.affiliation: Department of Obstetrics and Gynecology, Fetal Medicine Unit, University Hospital Brugmann, Université Libre de Bruxelles, Brussels, Belgium;
authors.forename: Jacques C
authors.initials: JC
authors.lastname: Jani
mesh_terms: D000402:Airway Obstruction / Q000378:metabolism*; D000818:Animals; D005333:Fetus / Q000378:metabolism; D065630:Hernias, Diaphragmatic, Congenital / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism; D011817:Rabbits; D012121:Respiration, Artificial / Q000379:methods; D014132:Trachea / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D054460:rho-Associated Kinases
keywords: TGF-β signaling; congenital diaphragmatic hernia; fetal tracheal occlusion; lung hypoplasia; rabbit model