Inhaled beclomethasone/formoterol in idiopathic pulmonary fibrosis: a randomised controlled exploratory study

Wright, Caroline; Fraser, Simon D.; Brindle, Kayleigh; Morice, Alyn H.; Hart, Simon P.; Crooks, Michael G.

doi:10.1183/23120541.00100-2017

Cited by 6 publications

(6 citation statements)

References 11 publications

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“…Interestingly, previous work has shown efficacy of β2adrenoceptor agonist olodaterol in an in vivo model of pulmonary fibrosis (Herrmann et al, 2017). Moreover, a trial examining the effect of combined treatment of beclomethasone, a corticosteroid, and formoterol, a long-acting β2-adrenoceptor agonist, in patients with IPF reported promising results, albeit in a small sample size (Wright et al, 2017). The efficacy of β2-adrenergic receptor agonism in these studies may be explained by the existence of a diversity of distinct fibroblast subtypes which contribute to pulmonary fibrosis (Habermann et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly one group also discovered that co-treatment with a corticosteroid, dexamethasone, rescued the loss of β2-adrenergic receptor mediated by TGF-β1 in ASMs. This offers another explanation to the observed benefits of combined treatment of beclomethasone, a corticosteroid, and formoterol, a long-acting β2-adrenoceptor agonist in IPF patients (Wright et al, 2017), although this would require further validation.…”

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confidence: 98%

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Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Gao

Espinosa

Nguyen

et al. 2023

J Pharmacol Exp Ther

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Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in idiopathic pulmonary fibrosis (IPF). This uncontrolled production of ECM is stimulated by mechanosignaling and TGF-β1 signaling which together promote transcriptional programs including Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). G protein-coupled receptors which couple to G alpha s have emerged as pharmacological targets to inactivate YAP/TAZ signaling and promote lung fibrosis resolution. Previous studies have shown a loss of expression of "antifibrotic GPCRs"-receptors which couple to G alpha s, in IPF patient-derived fibroblasts compared to non-IPF samples. Of the 14 G alpha s GPCRs we found to be expressed in lung fibroblasts, the dopamine receptor D1 (DRD1) was one of only two not repressed by TGF-β1 signaling, with the β2-adrenergic receptor being the most repressed. We compared the potency and efficacy of multiple D1 and β2 receptor agonists +/-TGF-β1 treatment in vitro for their ability to elevate cAMP, inhibit nuclear localization of YAP/TAZ, regulate expression of profibrotic and antifibrotic genes, and inhibit cellular proliferation and collagen deposition. Consistently, the activity of β2 receptor agonists was lost, while D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-β1. These data further support the therapeutic potential of the dopamine receptor D1 and highlight an orchestrated and pervasive loss of antifibrotic GPCRs mediated by TGF-β1 signaling.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Gao

Espinosa

Nguyen

et al. 2023

J Pharmacol Exp Ther

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“…Treatment with inhaled LABA/ICS (formoterol/ beclomethasone) has been tested in a 4-week pilot study of patients with IPF (Wright et al, 2017). LABA/ICS-treated patients had reductions in several readouts of coagulopathy and platelet activation, reduced sputum eosinophil counts, and improved 1second forced expiratory volume.…”

Section: Fibroblastsmentioning

confidence: 99%

“…The regulation of platelets by b-AR agonists is a potentially overlooked effect of inhaled LABAs, i.e., on platelets in the lung, especially in capillaries in the vicinity of alveoli, that merits further study. Patients with IPF show improvements in markers of coagulation and platelet activation after treatment with inhaled LABAs/ICS (Wright et al, 2017). Crosstalk between signaling pathways associated with inflammation may promote coagulation and pulmonary thromboinflammation in certain viral infections Insel, 2020b, Sriram andInsel, 2021).…”

Section: Plateletsmentioning

confidence: 99%

Inhaled β2 Adrenergic Agonists and Other cAMP-Elevating Agents: Therapeutics for Alveolar Injury and Acute Respiratory Disease Syndrome?

Sriram

Insel

2021

Pharmacol Rev

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Inhaled long-acting b-adrenergic agonists (LABAs) and short-acting b-adrenergic agonists are approved for the treatment of obstructive lung disease via actions mediated by b2 adrenergic receptors (b2-ARs) that increase cellular cAMP synthesis. This review discusses the potential of b2-AR agonists, in particular LABAs, for the treatment of acute respiratory distress syndrome (ARDS). We emphasize ARDS induced by pneumonia and focus on the pathobiology of ARDS and actions of LABAs and cAMP on pulmonary and immune cell types. b2-AR agonists/cAMP have beneficial actions that include protection of epithelial and endothelial cells from injury, restoration of alveolar fluid clearance, and reduction of fibrotic remodeling. b2-AR agonists/cAMP also exert antiinflammatory effects on the immune system by actions on several types of immune cells. Early administration is likely critical for optimizing efficacy of LABAs or other cAMP-elevating agents, such as agonists of other Gs-coupled G protein-coupled receptors or cyclic nucleotide phosphodiesterase inhibitors. Clinical studies that target lung injury early, prior to development of ARDS, are thus needed to further assess the use of inhaled LABAs, perhaps combined with inhaled corticosteroids and/or long-acting muscarinic cholinergic antagonists. Such agents may provide a multipronged, repurposing, and efficacious therapeutic approach while minimizing systemic toxicity.Significance Statement--Acute respiratory distress syndrome (ARDS) after pulmonary alveolar injury (e.g., certain viral infections) is associated with $40% mortality and in need of new therapeutic approaches. This review summarizes the pathobiology of ARDS, focusing on contributions of pulmonary and immune cell types and potentially beneficial actions of b2 adrenergic receptors and cAMP. Early administration of inhaled b2 adrenergic agonists and perhaps other cAMP-elevating agents after alveolar injury may be a prophylactic approach to prevent development of ARDS.

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“…The risk-bene t balance of ICS in ILDs, particularly in IPF, is still uncertain. A small previous study indicated that beclomethasone/formoterol improved lung function in patients with compared with a placebo [13], but its broader effects on IPF development, especially in patients with chronic airway diseases, are not well-understood. This study aimed to investigate the association between ICS use and the risk of IPF in patients with chronic airway disease using nationwide claims data.…”

mentioning

confidence: 99%

High Dose Inhaled Corticosteroid Increased the Incidence of Idiopathic Pulmonary Fibrosis: Nationwide Population based Study

Lee,

Yoon

2024

Preprint

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Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease found primarily in older people, with the use of systemic steroids linked to poor outcomes. However, role of inhaled corticosteroids (ICS) in IPF remains unclear. This This study investigated the association between ICS use and IPF risk using national insurance data, particularly in individuals with chronic airway diseases. Methods Utilising the National Health Insurance Service-National Sample Cohort database, our study included patients diagnosed with chronic obstructive pulmonary disease (COPD) or asthma. ICS exposure was assessed via treatment claims, and IPF cases were identified using broad and narrow criteria. We used inverse probability of treatment weighting (IPTW) with propensity scores for balanced covariate analysis. Results Of 57,456 patients (mean age: 55.9 years, 42.3% male), 16.5% used ICS and 83.5% did not. ICS users showed higher rates of broad (0.98 vs. 0.41 per 1,000) and narrow IPF (0.61 vs. 0.21 per 1,000) than non-users. Pre-IPTW, ICS use was associated with increased IPF risk; however, this was not significant post-IPTW. Post-IPTW, both continuous (broad adjusted hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 1.02–1.04; narrow adjusted HR per 100 µg/day: 1.03, 95% CI: 1.01–1.04 post-IPTW) and high-dose ICS (≥ 1000 µg/day) (broad adjusted HR: 3.89, 95% CI: 1.61–9.41; narrow adjusted HR: 3.99, 95% CI: 1.19–13.41) use correlated with an elevated IPF risk. Subgroup analysis revealed an increased risk in medically aided. Conclusion High-dose ICS use may be associated with elevated IPF risk, especially in patients receiving medical aid.

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Inhaled beclomethasone/formoterol in idiopathic pulmonary fibrosis: a randomised controlled exploratory study

Cited by 6 publications

References 11 publications

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Dopamine Receptor D1 Is Exempt from Transforming Growth Factorβ-Mediated Antifibrotic G Protein-Coupled Receptor Landscape Tampering in Lung Fibroblasts

Inhaled β2 Adrenergic Agonists and Other cAMP-Elevating Agents: Therapeutics for Alveolar Injury and Acute Respiratory Disease Syndrome?

High Dose Inhaled Corticosteroid Increased the Incidence of Idiopathic Pulmonary Fibrosis: Nationwide Population based Study

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