Glucocorticoid Modulation in Airway Smooth Muscle Function

Chronic airway disorders such as asthma and chronic obstructive pulmonary disease are fundamentally driven by dysregulated airway smooth muscle (ASM) contraction, proliferation and inflammation. Glucocorticoids are the principal anti-inflammatory agents in respiratory medicine, exerting their effects through binding to the glucocorticoid receptor (GR) in ASM cells. This interaction triggers genomic transactivation of anti-inflammatory genes and transrepression of pro-inflammatory transcription factors, notably NF-κB and AP-1, thereby reducing cytokine release and cellular recruitment. In parallel, glucocorticoids instigate non-genomic actions that modulate ion channel function and intracellular calcium dynamics, leading to attenuated ASM contractility. The induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) is a central mechanism by which glucocorticoids inhibit MAPK signalling, curbing ASM proliferation and hyperreactivity. Intriguingly, ASM cells can generate active glucocorticoids locally and regulate GR expression in an autocrine homeostatic loop, which may protect against pro-asthmatic stimuli. Clinically, combination therapy with long-acting β2-adrenoceptor agonists (LABAs) and inhaled corticosteroids (ICSs) produces synergistic bronchodilation and enhanced anti-inflammatory efficacy, owing to reciprocal upregulation of β2-receptors by steroids and potentiation of GR activation by β2-agonists. Ongoing research is unraveling the molecular circuitry underlying glucocorticoid sensitivity and resistance in ASM, with the aim of refining personalised treatment strategies and reducing the global burden of steroid-refractory airway disease.

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Glucocorticoid Modulation in Airway Smooth Muscle Function publication trend

The graph below shows the total number of articles in glucocorticoid modulation in airway smooth muscle function across all publications each year (not limited to Nature Index journals).

Technical terms

Airway smooth muscle (ASM): The specialised muscle lining bronchi and bronchioles, responsible for airway calibre through contraction and relaxation.

Glucocorticoids: Steroid hormones that bind to glucocorticoid receptors to modulate gene expression and suppress inflammation.

Glucocorticoid receptor (GR): A ligand-activated transcription factor that mediates the genomic and non-genomic actions of glucocorticoids.

Mitogen-activated protein kinase phosphatase-1 (MKP-1): A dual-specificity phosphatase induced by glucocorticoids that deactivates MAPK pathways to reduce inflammation.

Long-acting β2-adrenoceptor agonist (LABA): A bronchodilator that stimulates β2-receptors on ASM to induce relaxation over an extended period.

Inhaled corticosteroid (ICS): A formulation of glucocorticoid delivered directly to the airways to minimise systemic exposure while maximising local anti-inflammatory effects.

Cytokine: A small secreted protein that mediates intercellular communication in immune and inflammatory responses.

References

1. Homeostatic glucocorticoid signaling in airway smooth muscle: A roadmap to asthma pathogenesis. Frontiers in Endocrinology (2023).
2. Role and regulation of MKP-1 in airway inflammation. Respiratory Research (2017).
3. Beclomethasone dipropionate and formoterol fumarate synergistically interact in hyperresponsive medium bronchi and small airways. Respiratory Research (2018).
4. Inhibition of NF-κB-dependent Transcription by MKP-1 TRANSCRIPTIONAL REPRESSION BY GLUCOCORTICOIDS OCCURRING VIA p38 MAPK*. Journal of Biological Chemistry (2009).
5. Ligand-independent Activation of the Glucocorticoid Receptor by β2-Adrenergic Receptor Agonists in Primary Human Lung Fibroblasts and Vascular Smooth Muscle Cells*. Journal of Biological Chemistry (1999).
6. DUSP1 Maintains IRF1 and Leads to Increased Expression of IRF1-dependent Genes A MECHANISM PROMOTING GLUCOCORTICOID INSENSITIVITY*. Journal of Biological Chemistry (2016).