Upregulated expression of EGF and TGF-? in the proximal respiratory epithelium in the human hypoplastic lung in congenital diaphragmatic hernia

Abstract

Newborn infants with congenital diaphragmatic hernia (CDH) still have a high mortality rate. Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are peptide growth factors involved in the fetal lung growth and development. The EGF and TGF-alpha have been reported to promote pulmonary branching activity and alveolar type-II pneumocyte proliferation. Epidermal growth factor and TGF-alpha immunoreactivity and mRNA expression in the bronchial and bronchiolar epithelium is maximal during early fetal life and barely detectable in the proximal airways of neonatal lung. The purpose of this study was to determine protein and gene expression of EGF and TGF-alpha in CDH lung in order to elucidate the potential role of these growth factors in the pathogenesis of pulmonary hypoplasia in CDH. Lung tissue specimens were obtained from archival lung tissue from 11 patients with CDH and 5 controls. Indirect immunohistochemistry was performed using ABC method with anti-EGF and anti-TGF-alpha antibodies. In situ hybridization was performed using EGF and TGF-alpha specific digoxigenin-labeled oligonucleotide probes. The most striking difference between hypoplastic CDH lung and control lung was the strong EGF and TGF-alpha mRNA expression and immunoreactivity in the bronchial and bronchiolar epithelium in CDH lung. The upregulated protein and gene expression of EGF and TGF-alpha in the proximal airways in the CDH hypoplastic lung suggests persistence of fetal stage of pulmonary airway development in CDH.