Acceleration of alveolar type II cell differentiation in fetal rhesus monkey lung by administration of EGF

Abstract

To examine the effect of epidermal growth factor (EGF) on lung parenchymal maturation in fetal rhesus monkey, recombinant human EGF was administered intraperitoneally (IP) at 66 mg/kg body wt over a 7-day period into the fetal peritoneal cavity alone or IP and into the amniotic fluid (AF) simultaneously. The saline carrier was injected IP and AF into control (CO) fetuses. The body weights of the IP + AF group were significantly larger than CO. Overall lung growth, measured as wet lung weight or fixed volume of the right cranial lobe, was unchanged. Fixed lung volume per gram body weight was significantly lower for both IP + AF and IP compared with CO. Morphogenesis of lung parenchyma, measured as percent parenchymal airspace or airspace size, was unchanged. Alveolar type II cell ultrastructure was significantly altered by EGF treatment; volume fraction of cytoplasmic glycogen was 50% less and lamellar bodies threefold greater for IP + AF and IP groups compared with CO. Total phospholipid content of AF was not altered, but relative percentages of different phospholipids were changed by EGF treatments; phosphatidylinositol was significantly reduced, and phosphatidylglycerol was significantly elevated. The lecithin-to-sphingomyelin ratio was unchanged. Surfactant apoprotein A concentration in AF was significantly elevated and was detected by immunoperoxidase in more cuboidal alveolar cells in EGF-treated animals when compared with CO. We conclude that exogenous EGF administered in the last trimester of pregnancy accelerates structural and functional cytodifferentiation of the alveolar type II cell in fetal primates. These maturational changes occur in the absence of significant alterations in overall lung growth or morphogenesis of the gas exchange area.

Immunolocalization of Transforming Growth Factor-α, Epidermal Growth Factor (EGF), and EGF-Receptor in Normal and Injured Developing Human Lung

“…Their prominent localization in airway epithelium suggests a possible role in airway growth and epithelial cell differentiation and maturation. Many studies of pharmacologic treatment of developing lung with EGF have demonstrated potent effects on branching morphogenesis (14,20,21) and lung epithelial cell maturation (22)(23)(24)(25). Taken together, these studies indicate that EGF can exert effects on both lung morphogenesis and functional maturation of epithelial cells.…”

“…Also, inhibition of endogenous EGF production with an antisense oligonucleotide directed against EGF in fetal mouse lung explants reduced airway branching (21). Pharmacologic treatment of fetal rat, monkey, rabbit, and sheep lungs at various gestational ages with EGF results in accelerated type I1 cell differentiation, DNA synthesis, and surfactant production (22)(23)(24)(25).…”

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

“…All of them are mitogens in type II pneumocytes, and act synergistically to mediate their maturation and increase surfactant synthesis [8]. EGF had benefi cial eff ects in an animal model of ALI [39], and inhibition of EGF receptor had a detrimental eff ect during airway epithelium repair [40]. KGF has been linked to upregulation of anti-infl am matory cytokines and modulation of epithelial cell migration [41].…”

Prenatal Exposure to Epidermal Growth Factor Attenuates Respiratory Distress Syndrome in Rhesus Infants

“…We conclude that prenatal exposure to EGF stimulates biochemical and histologic maturation of the lung and markedly attenuates the clinical severity of respiratory disease in this model of simian respiratory distress syndrome. (1)(2)(3)(4)(5). EGF induces increased synthesis and secretion of surfactant and surfactant-associated proteins in these cells.…”