Glucocorticoids increase the risk of preterm premature rupture of membranes possibly by inducing ITGA8 gene expression in the amnion. (October 2022)

• Record Type: Journal Article
• Authors: Okazaki, Yuka; Taniguchi, Kosuke; Miyamoto, Yoshitaka; Kinoshita, Shiori; Nakabayashi, Kazuhiko; Kaneko, Kayoko; Hamada, Hiromi; Satoh, Toyomi; Murashima, Atsuko; Hata, Kenichiro
• Is Part Of: Placenta. Volume 128(2022)
• Page Start: 73
• Page End: 82
• Publication Date: 2022-10
• Subjects: Preterm premature rupture of membranes -- Glucocorticoid -- Cell adhesion -- ITGA8 -- Electric cell-substrate impedance sensing -- Transcriptomics; DEGs differentially expressed genes -- DEX dexamethasone -- ECIS electric cell-substrate impedance sensing -- ECM extracellular matrix -- FDR false-discovery rate -- GO gene ontology -- GR glucocorticoid receptor -- ITGA8 α8 integrin chain -- hAMCs human amnion cells -- NCCHD National Center for Child Health and Development -- pPROM preterm premature rupture of membranes -- RNA-seq RNA sequencing -- SD standard deviation -- SLE systemic lupus erythematosus -- SLEDAI SLE disease activity index; Placenta -- Periodicals; Reproduction -- Periodicals; Placenta -- Periodicals; Placenta -- Périodiques; Reproduction -- Périodiques; 612.63
• DOI: 10.1016/j.placenta.2022.07.012
• Languages: English
• ISSNs: 0143-4004

Abstract

Abstract: Introduction: Maternal glucocorticoid exposure increases the risk of preterm delivery; however, the association between glucocorticoids and preterm premature rupture of membranes (pPROM)—a direct cause of preterm delivery—has rarely been investigated. Methods: To examine this association, we evaluated the clinical data of patients with systemic lupus erythematosus (SLE). Mechanism analysis was performed in both human amnion-derived mesenchymal cells (as a model for fetal membranes) and the amnion from SLE patients. We characterized the effects of glucocorticoids on the amnion in both models through comprehensive gene expression profiling and by electric cell-substrate impedance sensing in the mesenchymal cells. Results: The average glucocorticoid dose in cases with pPROM (13.3 mg/day, n = 10) was significantly higher than in those without pPROM (8.5 mg/day, n = 65; P < 0.01) among pregnant patients with well-controlled SLE (SLEDAI <4, n = 75); however, we did not observe a statistically significant difference in it between cases with or without chorioamnionitis. Glucocorticoid-treated human amnion mesenchymal cells showed decreased electric resistance between cells, indicating increased permeability. Differentially expressed genes upon glucocorticoid treatment were significantly enriched with cell adhesion-related genes. Among them, ITGA8 was strikingly induced in both the amnion mesenchymal cells and in amnion derived from patients with SLE. Discussion: We observed an association between glucocorticoids and pPROM with non-infectious etiology. Our findings indicate that glucocorticoids increase amnion permeability and modulate cell-adhesion related genes. ITGA8 represents a primary molecule that triggers pPROM through fibrotic remodeling and preventing resealing of the rupture site in fetal amnion. Highlights: Glucocorticoid use was not only associated with preterm birth but also with pPROM. Glucocorticoid-associated pPROM had non-infectious etiologies. Glucocorticoid exposure increased permeability of fetal membranes. Glucocorticoids modulated expression of cell adhesion genes in fetal membranes. ITGA8 represents a primary candidate molecule elevating susceptibility to pPROM.