Glucocorticoids and the Lung

Abstract

The lung is a major clinical target of glucocorticoid-based therapeutics, and GR signaling has broad effects on respiratory physiology and inflammation. During lung development, expression of GR in the mesenchyme is required for normal terminal alveolar epithelial differentiation. Prenatal administration of exogenous glucocorticoids (GCs) to prevent neonatal respiratory distress syndrome, however, promotes alveolar maturation and accelerates surfactant expression in a manner consistent with direct effects on the developing alveolar epithelium. Likewise, cell autonomous effects of GCs in regulating gene expression and phenotype of the airway epithelium and airway smooth muscle have been demonstrated to control important therapeutic effects of GCs in treating asthma and chronic obstructive pulmonary disease. Here, mechanisms and consequences of GR signaling in the developing lung and in treating obstructive lung disease are reviewed, with a focus on direct effects of GR signaling on alveolar differentiation, surfactant expression, and airway epithelial and smooth muscle pathophysiology.

Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression

“…Glucocorticoids play a crucial role in normal physiology and are highly effective anti-inflammatory drugs with diverse clinical indications including asthma, rheumatoid arthritis, lupus, and inflammatory bowel disease, among many others (Morand 2000;Barnes 2006;Gerber 2015;Kim et al 2017). Glucocorticoids exert their potent effects through binding to the glucocorticoid receptor (NR3C1, also known as the GR), which causes the GR to translocate to the nucleus and regulate gene expression through directly interacting with specific DNA sequences (Meijsing 2015;Sacta et al 2016).…”

Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects

“…One of the major targets of GCs in obstructive airway diseases such as asthma is the airway epithelium (24). The airway epithelium engages in complex pathophysiologic cross-talk with immune cells (25,26), which are themselves GC targets, and infectious and environmental stimuli (27)(28)(29), ultimately leading to airway inflammation and symptoms in susceptible patients (30).…”

Nascent transcript analysis of glucocorticoid crosstalk with TNF defines primary and cooperative inflammatory repression

“…To determine mechanisms and targets through which ligand-activated GR represses gene expression, we performed GRO-seq on Beas-2B airway epithelial cells treated for 10 and 30 minutes with vehicle (ethanol), TNF, dex or TNF and dex in combination. Airway epithelial cells were selected for these experiments as they are a target of glucocorticoid treatment in highly prevalent diseases such as asthma and chronic obstructive pulmonary disease (Gerber 2015).…”

“…Glucocorticoids play a crucial role in normal physiology and are highly effective antiinflammatory drugs with a remarkable range of clinical indications including asthma, rheumatoid arthritis, lupus, inflammatory bowel disease, psoriasis, and vasculitis, among others (Morand 2000;Barnes 2006;Gerber 2015;Kim et al 2017). Glucocorticoids exert their potent biological and pharmacological effects through binding to the glucocorticoid receptor (GR), which causes GR to translocate to the nucleus and regulate gene expression through directly interacting with specific DNA sequences (Meijsing 2015;Sacta et al 2016).…”