Abstract
Newborn infants with congenital diaphragmatic hernia (CDH) still have a high mortality rate. Epidermal growth factor (EGF) and transforming growth factor-α (TGF-α) are peptide growth factors involved in the fetal lung growth and development. The EGF and TGF-α have been reported to promote pulmonary branching activity and alveolar type-II pneumocyte proliferation. Epidermal growth factor and TGF-α 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-α 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-α antibodies. In situ hybridization was performed using EGF and TGF-α specific digoxigenin-labeled oligonucleotide probes. The most striking difference between hypoplastic CDH lung and control lung was the strong EGF and TGF-α mRNA expression and immunoreactivity in the bronchial and bronchiolar epithelium in CDH lung. The upregulated protein and gene expression of EGF and TGF-α in the proximal airways in the CDH hypoplastic lung suggests persistence of fetal stage of pulmonary airway development in CDH.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Puri P (1994) Congenital diaphragmatic hernia. Curr Prob Surg 31:785–856
Blackburn WR, Logsdon P, Alexaander JA (1977) Congenital diaphragmatic hernia: studies of lung composition and structure. Am Rev Respir Dis 115 (Suppl):275
George DK, Cooney TP, Chiu BK, Thurlbeck WM (1987) Hypoplasia and immaturity of the terminal lung unit (acinus) in congenital diaphragmatic hernia. Am Rev Respir Dis 136:947–950
Stiles AD, Smith BT, Post M (1986) Reciprocal autocrine and paracrine regulation of growth of mesenchymal and alveolar epithelial cells from fetal lung. Exp Lung Res 11:165–177
King RJ, Jones MB, Minoo P (1989) Regulation of lung cell proliferation by polypeptide growth factors. Am J Physiol 257:L23–L38
Oue T, Shima H, Taira Y, Puri P (2000) Administration of antenatal glucocorticoids upregulates peptide growth factor gene expression in nitrofen-induced congenital diaphragmatic hernia in rats. J Pediatr Surg 35:109–122
Jesudason EC, Connell MG, Fernig DG, Lloyd DA, Losty PD (2000) In vitro effects of growth factors on lung hypoplasia in a model of congenital diaphragmatic hernia. J Pediatr Surg 35:914–922
Miyazaki E, Ohshiro K, Taira Y, Puri P (1998) Altered insulin-like growth factor I mRNA expression in human hypoplastic lung in congenital diaphragmatic hernia. J Pediatr Surg 33:1476–1479
Goldin GV, Opperman LA (1980) Induction of supernumerary tracheal buds and the stimulation of DNA synthesis in the embryonic chick lung and trachea by epidermal growth factor. J Embryol Exp Morphol 60:235–243
Warburton D, Seth R, Shum L, Horcher PG, Hall FL, Werb Z, Slavkin HC (1992) Epigenetic role of epidermal growth factor expression and signaling in embryonic mouse lung morphogenesis. Dev Biol 149:123–133
Ganster GL, Stricklin GP, Matrisian LM (1991) EGF and TGF-α influence in vitro lung development by the induction of matrix-degrading metalloproteinases. Int J Dev Biol 35:453–461
Catterton WZ, Escobedo MB, Sexson WR, Gray ME, Sundell HW, Stahlman MT (1979) Effect of epidermal growth factor on lung maturation in fetal rabbits. Pediatr Res 13:104–108
Sundell HW, Gray ME, Serenius FS, Escobedo MB, Stahlman MT (1980) Effects of human epidermal growth factor on lung maturation in fetal lambs. Am J Pathol 100:707–725
Plopper CG, St. George JA, Read LC, Nishio SJ, Weir AJ, Edwards L, Tarantal AF, Pinkerton KE, Merritt TA, Whitsett JA (1992) Acceleration of alveolar type-II cell differentiation in fetal rhesus monkey lung by administration of EGF. Am J Physiol 262:L313–L321
Raaberg L, Nexo E, Jorgensen PE, Poulsen SS, Jakab M (1995) Fetal effects of epidermal growth factor deficiency induced in rats by autoantibodies against epidermal growth factor. Pediatr Res 37:175–181
Stahlman MT, Orth DN, Gray ME (1989) Immunocytochemical localization of epidermal growth factor in the developing human respiratory system and in acute and chronic lung disease in the neonate. Lab Invest 60:539–547
Strandjord TP, Clark JG, Guralnick DE, Madtes DK (1995) Immunolocalizazion of transforming growth factor-α, epidermal growth factor (EGF), and EGF-receptor in normal and injured developing human lung. Pediatr Res 38:851–856
Oshiro K, Puri P (1998) Increased insulin-like growth factor-I mRNA expression in pyloric muscle in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 13:253–255
Ruocco S, Lallemand A, Tournier JM, Gaillard D (1996) Expression and localization of epidermal growth factor, transforming growth factor-α, and localization of their common receptor in fetal human lung development. Pediatr Res 39:448–455
Lee RM, O’Brodovich H (1988) Airway epithelial damage in premature infants with respiratory failure. Am Rev Respir Dis 137:450–457
Bos AP, Hussain SM, Hazebroek FWJ, Tibboel D, Meradji M, Molenaar JC (1993) Radiographic evidence of bronchoplumonary dysplasia in high-risk congenital diaphragmatic hernia survivors. Pediatr Pulmonol 15:231–235
Khoor A, Gray ME, Hull WM, Whitsett JA, Stahlman MT (1993) Developmental expression of SP-A and SP-A mRNA in the proximal and distal respiratory epithelium in the human fetus and newborn. J Histochem Cytochem 41:1311–1319
Klein JM, Mc Carthy TA, Dagle JM, Snyder JM (2000) Antisense inhibition of epidermal growth factor receptor decreases expression of human surfactant protein A. Am J Respir Cell Mol Biol 22:676–684
Asabe K, Tsuji K, Handa N, Kurosaka N (1997) Immunohistochemical distribution of surfactant apoprotein-A in congenital diaphragmatic hernia. J Pediatr Surg 32:667–672
Guarino N, Oue T, Shima H, Puri P (2000) Antenatal dexamethasone enhances surfactant protein synthesis in the hypoplastic lung of nitrofen-induced diaphragmatic hernia in rats. J Pediatr Surg 35:1468–1473
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Guarino, N., Solari, V., Shima, H. et al. Upregulated expression of EGF and TGF-α in the proximal respiratory epithelium in the human hypoplastic lung in congenital diaphragmatic hernia. Ped Surgery Int 19, 755–759 (2004). https://doi.org/10.1007/s00383-003-1052-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00383-003-1052-z