Oxygen and steroids affect the regulatory role of natriuretic peptide receptor-C on surfactant secretion by type II cells

• Published in: American journal of physiology. Lung cellular and molecular physiology 2022-01, Vol.322 (1), p.L13-L22
• Main Authors: Ryan, Rita M, Paintlia, Manjeet K, Newton, Danforth A, Spyropoulos, Demetri D, Kemp, Matthew, Jobe, Alan H, Baatz, John E
• Format: Article
• Language: English
• Subjects: Adult; Alveolar Epithelial Cells - drug effects; Alveolar Epithelial Cells - metabolism; Alveoli; Animals; Atrial Natriuretic Factor - metabolism; Atrial natriuretic peptide; Betamethasone - pharmacology; Body Fluids - metabolism; Cell culture; Cell Line; Dexamethasone; Dexamethasone - pharmacology; Epithelial cells; Epithelium; Fetuses; Glucocorticoids - pharmacology; Humans; Lung - embryology; Lung - metabolism; Lungs; Mice; Models, Biological; Neonates; Oxygen; Oxygen - pharmacology; Peptides; Pulmonary Surfactants - metabolism; Receptors; Receptors, Atrial Natriuretic Factor - genetics; Receptors, Atrial Natriuretic Factor - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Secretion; Sheep; siRNA; Steroid hormones; Steroids; Steroids - pharmacology; Surfactants; Terbutaline; Terbutaline - pharmacology; Transfection
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00300.2021

Atrial natriuretic peptide (ANP) and its receptors natriuretic peptide receptor (NPR)-A and NPR-C are all highly expressed in alveolar epithelial type II cells (AEC2s) in the late-gestation ovine fetal lung and are dramatically decreased postnatally. However, of all the components, NPR-C stimulation inhibits ANP-mediated surfactant secretion. Since alveolar oxygen increases dramatically after birth, and steroids are administered to mothers antenatally to enhance surfactant lung maturity, we investigated the effects of O concentration and steroids on NPR-C-mediated surfactant secretion in AEC2s. NPR-C expression was highest at 5% O while being suppressed by 21% O , in cultured mouse lung epithelial cells (MLE-15s) and/or human primary AEC2s. Surfactant protein-B (SP-B) was significantly elevated in media from both in vitro and ex vivo culture at 13% O versus 21% O in the presence of ANP or terbutaline (TER). Both ANP and C-ANP (an NPR-C agonist) attenuated TER-induced SP-B secretion; this effect was reversed by dexamethasone (DEX) pretreatment in AEC2s and by transfection with NPR-C siRNA in MLE-15 cells. DEX markedly reduced AEC2 NPR-C expression, and pregnant ewes treated with betamethasone showed reduced ANP in fetal sheep lung fluid. These data suggest that elevated O downregulates AEC2 NPR-C and that steroid-mediated NPR-C downregulation in neonatal lungs may provide a novel mechanism for their effect on perinatal surfactant production.