Effect of epidermal growth factor on lung growth in experimental fetal pulmonary hypoplasia

doi:10.1016/S0378-3782(99)00052-3

Early Human Development

Volume 57, Issue 1, January 2000, Pages 61-69

https://doi.org/10.1016/S0378-3782(99)00052-3 Get rights and content

Abstract

The purpose of this study was (1) to compare the expression of epithelial growth factor receptor (EGFR) in the lung tissues of human fetuses with or without pulmonary hypoplasia, and (2) to investigate the effects of EGF on lung growth in experimental pulmonary hypoplasia in rabbits. Firstly, we investigated the expression of EGFR in lung tissues of human fetuses with or without pulmonary hypoplasia by immunohistochemistry. Secondly, the amniotic fluid was shunted into the maternal abdominal cavity in a group of 12 fetal rabbits, another group (n=12) received EGF injection (5 μg, i.p.) at day 25 of gestation. The third group (n=12) was only treated with EGF while littermates not operated on served as the control group (n=12). On day 29 of gestation, fetuses were delivered by Cesarean section and the lungs removed. The body weight and wet lung and liver weights were measured. As a measure of fetal lung growth, we determined the size of lung acini, the number of terminal airspaces, and diameter of alveoli (n=6, each groups). We also measured the concentration of phosphatidylcholine (PC) and the lecithin/sphingomyelin (L/S) ratio in lung lavage fluid at birth in some fetuses (n=6, each groups). In human fetuses with pulmonary hypoplasia, there was a significant decrease in radial alveolar count and expression of EGFR compared with fetuses without pulmonary hypoplasia. Amniotic shunt significantly decreased fetal lung/body weight ratio compared with control. Injection of EGF in the shunted group significantly increased lung/body weight ratio to the control level. The concentration of PC and L/S ratio in lung fluid lavage from rabbit fetuses with hypoplastic lungs was significantly higher than the other three groups. Histopathological examination of fetuses with hypoplastic lungs treated with EGF showed no significant change in the size of acini, number of terminal airspaces or the diameter of alveoli compared with the control group. Our results suggested that EGF was associated with lung growth and maturation of human lung and that treatment of rabbit fetuses with hypoplastic lungs with EGF facilitated lung growth and development.

Introduction

Fetal pulmonary hypoplasia is a condition characterized by a decrease in the number of lung cells, airways, and alveoli, associated with a decrease in organ size and weight. The condition usually develops as a complication of prolonged severe oligohydramnios caused by bilateral renal agenesis, infantile polycystic kidneys, prolonged leakage of amniotic fluid or congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia can be potentially fatal because it is associated with an inadequate surface area for gas exchange. Cases of pulmonary hypoplasia, defined as a low lung weight to body weight ratio [1], account for about 10% of all autopsy cases of stillbirth and neonatal diseases for neonates [2]. Therefore, it is important to clarify the pathogenesis of pulmonary hypoplasia.

Recent studies have shown that tracheal ligation in utero can counteract pulmonary hypoplasia associated with CDH, making it a potential modality to treat CDH antenatally [3], [4]. However, Papadakies et al. [5] reported that replacement of tracheal fluid with saline inhibits lung hypertrophy seen after tracheal ligation. This finding suggested that a growth factor in tracheal fluid may play an important role in the initiation of lung cell proliferation.

Epidermal growth factor (EGF) is a biologically active polypeptide first described in 1962 by Cohen [6] The biologic effects of EGF are primarily those of generalized epithelial growth and keratinization. In 1975, it was proposed that since EGF is a normal fetal growth hormone, it might also stimulate the growth of pulmonary epithelial cells [7]. To this effect, EGF is known to stimulate epithelial growth in several tissues and provide protection against the development of hyaline membrane disease in fetal lambs [8].

The objectives of the current study were (1) to carry out a preliminary examination the expression of EGFR in human lung tissues with or without pulmonary hypoplasia, and (2) to investigate the effects of EGF on lung growth in experimental pulmonary hypoplasia in rabbits.

Section snippets

Expression of EGFR in human fetuses

A total of 25 successive autopsy cases of stillbirth and early neonatal death (pulmonary hypoplasia: 15 cases; non-pulmonary hypoplasia: ten cases) at Nagasaki University Hospital from 1986 to 1997 were studied. All cases used for this study were adequate for morphological examination as well as immunohistochemical staining, and were not associated with marked pneumonia, hemorrhage, fibrosis, or hyaline membrane disease. The study protocol was approved by the Human Ethics Review Committee of

Expression of EGFR in human fetuses

Staining for EGFR was detected on the basement membrane of epithelial cells of respiratory bronchioles. Histopathologic and immunohistochemical examination of fetuses with pulmonary hypoplasia showed a significant decrease in radial alveolar count and expression of EGFR relative to those in fetuses without pulmonary hypoplasia (Table 1, Fig. 1).

Discussion

Very little is known about the exact mechanisms of lung growth after tracheal obstruction. A pressure phenomenon has been postulated, through as yet undefined pulmonary stretch receptors [14]. Recently, Papadakies et al. [5] reported that replacement of tracheal fluid with saline inhibits lung hypertrophy seen after tracheal ligation. Indeed, lung weight after ligation and saline replacement was not significantly different from that of unobstructed control. This indicates that tracheal fluid

Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research (No. 10671556) from the Ministry of Education, Science and Culture, Japan.

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Effect of epidermal growth factor on lung growth in experimental fetal pulmonary hypoplasia

Abstract

Introduction

Section snippets

Expression of EGFR in human fetuses

Expression of EGFR in human fetuses

Discussion

Acknowledgements

J Pediatr Surg

J Pediatr Surg

J Biol Chem

Am J Obstet Gynecol

Pulmonary hypoplasia: lung weight and radial alveolar count as criteria of diagnosis

Arch Dis Child

Anomalies associated with pulmonary hypoplasia

Am Rev Respir Dis

Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia

J Pediatr Surg

Interaction of epidermal growth factor (EGF) with cultured fibroblast

Adv Metab Disord

Effect of epidermal growth factor on lung maturation in fetal lamb

Am J Pathol