Pulmonary GLP-1 Receptor Increases at Birth and Exogenous GLP-1 Receptor Agonists Augmented Surfactant-Protein Levels in Litters From Normal and Nitrofen-Treated Pregnant Rats

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is found in a variety of tissues outside of the pancreas. For example, GLP-1R is expressed in the lung, where it has been implicated in the regulation of the lipid fraction of surfactants, suggesting it fulfills an important role in lung function. Here, we show that GLP-1R expression is strongly up-regulated immediately after birth in neonatal rats, particular in male offspring. Moreover, administering long half-life GLP-1R agonists to the mother from gestational day 14 to birth (exendin-4 or liraglutide) increased surfactant protein (SP)-A and SP-B mRNA expression and the amount of SPs in the amniotic fluid at the end of pregnancy. These effects were similar or more potent to those induced by the glucocorticoid dexamethasone, which also increased GLP-1R expression in fetuses just before delivery. Lir increased fetal SP-A and GLP-1R expression in control rats and in a nitrofen-induced model of lung hypoplasia. Moreover, lung size increased in controls after Lir administration, which also prevented the decrease in lung weight and the poor neonatal survival of the offspring from nitrofen-treated dams, effects that were not produced by dexamethasone. Taken together, our results demonstrate the importance of the GLP-1 system in regulating SP production and lung development.

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia

“…In contrast to what was observed in nitrofen-exposed rats with CDH, we could not demonstrate any beneficial effects of GLP-1 on airway morphometry [24]. However, vascular morphometry in peripheric pulmonary vessels improved in particular in the category of 30-60 µm vessels.…”

“…In a previous study by Romaní-Pérez et al [24], fetal rats with hypoplastic lungs given transplacental GLP-1 had a reversal in pulmonary hypoplasia with an increase in SPB expression. We repeated this experiment in rabbits and administered the maximal GLP-1 dose tolerated by the does.…”

“…Adult rat and human type 2 pneumocytes show increased surfactant protein secretion in the presence of GLP-1 (7-36) amide [22,23]. Transplacental administration of GLP-1 in a teratogenic model (nitrofen rat) of CDH showed an improvement in fetal lung-to-body-weight ratio (LBWR) and survival [24]. In particular, surfactant mRNA protein A and B were upregulated as a result of treatment [24].…”

“…Transplacental administration of GLP-1 in a teratogenic model (nitrofen rat) of CDH showed an improvement in fetal lung-to-body-weight ratio (LBWR) and survival [24]. In particular, surfactant mRNA protein A and B were upregulated as a result of treatment [24]. Pulmonary surfactant, produced by type 2 pneumocytes at the alveolar interface, consists of phospholipids and proteins responsible for preventing alveolar collapse [25].…”

Vildagliptin promotes improvement in pulmonary arterial hypertension: incretin-based therapy at a follow-up of 3 years

“…In addition to several important metabolites, GLP-1 presents some pleiotropic effects that are still little known. Studies show that GLP1 in the lungs increases the production of surfactant [14], acts as an anti-inflammatory in acute respiratory failure [15], and also promotes vasorelaxation in the pulmonary artery [7,8].…”