Abstract
The effect of endogenous progesterone and/or exogenous pre- or postnatal progesterone application on lung function of preterm infants is poorly defined. While prenatal progesterone substitution may prevent preterm birth, in vitro and in vivo data suggest a benefit of postnatal progesterone replacement on the incidence and severity of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms responsible for progesterone’s effects are undefined. Numerous factors are involved in lung development, airway inflammation, and airway remodeling: the transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog (Smad) signaling pathway and TGF-β-regulated genes, such as connective tissue growth factor (CTGF), transgelin (TAGLN), and plasminogen activator inhibitor-1 (PAI-1). These processes contribute to the development of BPD. The aim of the present study was to clarify whether progesterone could affect TGF-β1-activated Smad signaling and CTGF/transgelin/PAI-1 expression in lung epithelial cells. The pharmacological effect of progesterone on Smad signaling was investigated using a TGF-β1-inducible luciferase reporter and western blotting analysis of phosphorylated Smad2/3 in A549 lung epithelial cells. The regulation of CTGF, transgelin, and PAI-1 expression by progesterone was studied using a promoter-based luciferase reporter, quantitative real-time PCR, and western blotting in the same cell line. While progesterone alone had no direct effect on Smad signaling in lung epithelial cells, it dose-dependently inhibited TGF-β1-induced Smad3 phosphorylation, as shown by luciferase assays and western blotting analysis. Progesterone also antagonized the TGF-β1/Smad-induced upregulation of CTGF, transgelin, and PAI-1 at the promoter, mRNA, and/or protein levels. The present study highlights possible new molecular mechanisms involving progesterone, including inhibition of TGF-β1-activated Smad signaling and TGF-β1-regulated genes involved in BPD pathogenesis, which are likely to attenuate the development of BPD by inhibiting TGF-β1-mediated airway remodeling. Understanding these mechanisms might help to explain the effects of pre- or postnatal application of progesterone on lung diseases of preterm infants.
Highlights
The steroid progesterone is one of the most important hormones which maintain pregnancy [1]
Effect of progesterone on Smad signaling in lung epithelial cells To analyze the possible effect of progesterone on Smad signaling in lung epithelial cells, a TGF-β1-sensitive (CAGA)12-luciferase construct was transfected into A549 cells
The results showed that progesterone alone had no effect on Smad2/3 phosphorylation, while progesterone inhibited TGF-β1-induced Smad2/3 phosphorylation (Fig 2B)
Summary
The steroid progesterone is one of the most important hormones which maintain pregnancy [1]. Progesterone reduces neonatal morbidity and morbidity/mortality of preterm infants, lowers the incidence of respiratory distress syndrome, and reduces the need for mechanical ventilation and intensive care unit admissions [2]. Replacement of estradiol and progesterone in preterm infants tailored to maintain high intra uterine estradiol and progesterone levels is associated with tendency towards a reduced incidence of bronchopulmonary dysplasia (BPD) [3, 4]. BPD remains a major challenge for preterm infants [5, 6]. This chronic lung disease is characterized by a disruption of normal lung development, leading to fewer but larger alveoli, and a simplification of lung vessels [5, 6]. BPD is multifactorial, combining extreme lung immaturity with lung injury which implicate inflammatory and remodeling reactions evoked by mechanical ventilation, oxygen stress, and/or infection [5, 6]
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