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Decreased Lung Fibroblast Growth Factor 18 and Elastin in Human Congenital Diaphragmatic Hernia and Animal Models

¹ INSERM, U841, Institut Mondor de Médecine Moléculaire, and ² Faculté de Médecine, IFR10, Université Paris 12, Créteil, France; ³ Maternité and ⁴ Service de Fœtopathologie, Faculté de Médecine, AP-HP, Université Paris-Descartes, Hôpital Necker-Enfants Malades, Paris, France; and ⁵ Division of Neonatology, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada

Correspondence and requests for reprints should be addressed to Jacques Bourbon, Ph.D., Inserm U841, Université Paris 12, Faculté de Médecine, 8 rue du Général Sarrail, 94010 Créteil, France. E-mail: jacques.bourbon{at}creteil.inserm.fr

Rationale: Lung hypoplasia in congenital diaphragmatic hernia (CDH) seems to involve impaired alveolar septation. We hypothesized that disturbed deposition of elastin and expression of fibroblast growth factor 18 (FGF18), an elastogenesis stimulus, occurs in CDH.

Objectives: To document FGF18 and elastin in human CDH and ovine surgical and rat nitrofen models and to use models to evaluate the benefit of treatments.

Methods: Human CDH and control lungs were collected post mortem. Diaphragmatic hernia was created in sheep at 85 days; fetal lungs were collected at 139 days (term = 145 days). Pregnant rats received nitrofen at 12 days; fetal lungs were collected at 21 days (term = 22 days). Some of the sheep fetuses with hernia underwent tracheal occlusion (TO); some of the nitrofen-treated pregnant rats received vitamin A. Both treatments are known to promote lung growth.

Measurements and Main Results: Coincidental with the onset of secondary septation, FGF18 protein increased threefold in control human lungs, which failed to occur in CDH. FGF18 labeling was found in interstitial cells of septa. Elastin staining demonstrated poor septation and markedly decreased elastin density in CDH lungs. Consistently, lung FGF18 transcripts were diminished 60 and 83% by CDH in sheep and rats, respectively, and elastin density and expression were diminished. TO and vitamin A restored FGF18 and elastin expression in sheep and rats, respectively. TO restored elastin density.

Conclusions: Impaired septation in CDH is associated with decreased FGF18 expression and elastic fiber deposition. Simultaneous correction of FGF18 and elastin defects by TO and vitamin A suggests that defective elastogenesis may result, at least partly, from FGF18 deficiency.

Key Words: alveolarization • tracheal occlusion • nitrofen • vitamin A

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The pathogenesis of lung hypoplasia in congenital diaphragmatic hernia (CDH) remains imperfectly understood. What This Study Adds to the Field Impaired septation in CDH is associated with decreased FGF18 expression and elastin deposition. Simultaneous correction of FGF18 and elastin defects by tracheal occlusion suggests that defective elastogenesis may result in part from FGF18 deficiency.

 

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