Corticosteroid resistance in asthma: Cellular and molecular mechanisms

Caramori, Gaetano; Nucera, Francesco; Mumby, Sharon; Bello, Federica Lo; Adcock, Ian M.

doi:10.1016/j.mam.2021.100969

Cited by 28 publications

(20 citation statements)

References 235 publications

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“…One of the major issues faced by patients with severe asthma (5-10%) is their poor response to the current asthma management guideline therapies that include GCs ( 21 ). The underlying mechanisms driving this poor response to GCs have not been identified although defects in the cellular response to GCs in both immune ( 22 ) and lung structural cells ( 23 ) have been proposed. The link between mast cells and a poor response to asthma medication can be implied from studies showing that omalizumab therapy can improve not only asthma symptoms (and pulmonary function) but also reduce the need for high dose inhaled or oral GCs ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

“…We made the observation that GC insensitivity present in ASM cells derived from severe asthma was also reported to be gene-specific with CCL5, IL-6 and CCL11 being resistant to dexamethasone (or fluticasone), while CXCL10 still being repressed by either GCs ( 17 , 39 , 41 ). These results suggest that mast cell mediators repressed some but not all anti-inflammatory mechanisms driven by the GC receptor (GRα) which involve two main mechanisms that include transactivation (i.e., ability of GCs to induce expression of anti-inflammatory proteins) to an transrepression (i.e., ability to interfere with the expression of pro-inflammatory mediators) ( 22 ). Transactivation was shown to play an essential role in the therapeutic action of GCs in various cell types including ASM cells ( 42 ), where induction of some anti-inflammatory proteins such as TSC22D3 (GILZ) and DUSP1 (MKP1) were reported to mediate the inhibitory actions of GCs ( 43 – 45 ).…”

Section: Discussionmentioning

confidence: 99%

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Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells

et al. 2021

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The mechanisms underlying corticosteroid insensitivity in severe asthma have not been elucidated although some indirect clinical evidence points toward a role of mast cells. Here, we tested the hypothesis that mast cells can drive corticosteroid insensitivity in airway smooth muscle cells, a key player in asthma pathogenesis. Conditioned media from resting or FcεR1-activated human lung mast cells were incubated with serum-deprived ASM cells (1:4 dilution, 24 h) to determine their impact on the anti-inflammatory action of fluticasone on ASM cell chemokine expression induced by TNFα (10 ng/ml). Conditioned media from FcεR1-activated mast cells (but not that from non-activated mast cells or control media) significantly reduced the ability of 100 nM fluticasone to suppress ASM TNFα-dependent CCL5 and CXCL10 production at both mRNA and protein levels. In contrast, fluticasone inhibition of CXCL-8 production by TNFα was still preserved in the presence of activated mast cell conditioned media. Transcriptomic analysis validated by individual qPCR assays revealed that activated mast cell conditioned media dramatically reduced the number of anti-inflammatory genes induced by fluticasone in ASM cells. Our study demonstrates for the first time that conditioned media from FcεR1-activated mast cells blunt the anti-inflammatory action of corticosteroids in ASM cells by altering their transactivation properties. Because infiltration of mast cells within the ASM bundles is a defining feature of asthma, mast cell-derived mediators may contribute to the glucocorticoid insensitivity present in severe asthma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells

et al. 2021

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“…Several molecular mechanisms have been identified that may contribute to the resistance of cells to the anti-inflammatory effects of corticosteroids in severe asthma, with mechanisms differing between patients [62]. Glucocorticoid (GC) resistance may result from defects at different levels in GC signaling, such as reduced glucocorticoid receptor (GR) expression, reduce GC binding to GR, impaired nuclear translocation, or altered cofactor activity [63,64]. From a clinical point of view, it is important to consider that OCS may interfere with the correct detection of available and validated biomarkers as FeNO and blood eosinophils.…”

Section: Oral Corticosteroids (Ocs)-dependent Patientsmentioning

confidence: 99%

Severe Asthma and Biologics: Managing Complex Patients

Matucci¹,

Micheletto²,

Vultaggio³

2023

J Investig Allergol Clin

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Bronchial asthma is a chronic airway inflammatory disease of the respiratory tract that varies in terms of clinical presentations (phenotypes) and distinct underling pathophysiological mechanisms (endotypes). The definition of phenotype/endotype is crucial tak-ing into account the availability of novel biologic agent dedicated to patients who do not respond to conventional therapies. Although patients suffering from type 2 severe asthma significantly benefit from treatment with biologics no responders patients have been identified. Comorbidities increase the symptoms of asthma and complicate the overall management of the disease. The assessment and treatment of comorbidities is a crucial step and they the appropriate management may improve asthma symptoms and morbidity. Among comorbidities certainly chronic rhinosinusit with nasal polyps, obesity, bronchiectasis and immune defects represent a group of clinical conditions that negatively impact on asthma control despite a correct treatment. Although asthma is frequently characterized by an increase of blood eosinophils that releasing mediators and cytokines are involved in the inflammatory processes of airways wall, in patients with very high blood eosinophil levels it is opportune to be very careful in discerning whether it is a case of isolated severe eosinophilic asthma or a case of asthma in EGPA disease. In addition, hypereosinophilia can be the consequence of specific biological treatment as in the case of dupilumab. In this paper we have outlined the clinical features of those patients with severe asthma in which the management of the disease can be more complex.

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“…The mechanism of action of corticosteroids in lung diseases with a high inflammatory burden is still poorly understood, but their efficacy is reasonably linked to their anti-inflammatory properties [ 51 ]. The physiological actions of corticosteroids are carried out by a genomic and non-genomic mechanism [ 52 ].…”

Section: Anti-inflammatory Properties Of Inhaled Corticosteroids (Icss)mentioning

confidence: 99%

Inhaled Corticosteroids in Adults with Non-cystic Fibrosis Bronchiectasis: From Bench to Bedside. A Narrative Review

Martínez‐García

Oscullo

García-Ortega

et al. 2022

Drugs

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Due to their potent anti-inflammatory capacity (particularly in predominantly eosinophilic inflammation) and immunosuppressive properties, inhaled corticosteroids (ICSs) are widely used in asthmatic patients and also in individuals with chronic obstructive pulmonary disease (COPD) who suffer multiple exacerbations or have peripheral eosinophilia. However, there is little evidence for their use in non-cystic fibrosis bronchiectasis (hereafter, bronchiectasis). According to data extracted from large databases of bronchiectasis in adults, ICSs are used in more than 50% of patients without any scientific evidence to justify their efficacy and contrary to the recommendations of international guidelines on bronchiectasis that generally advise against their use. Indeed, bronchiectasis is a disease with predominantly neutrophilic inflammation and a high likelihood of chronic bacterial bronchial infection. Furthermore, it is known that due to their immunosuppressive properties, ICSs can induce an increase in bacterial infections. This manuscript aims to review the basic properties of ICSs, how they impact bronchiectasis in adults, the current position of international guidelines on this treatment, and the current indications and future challenges related to ICS use in bronchiectasis.

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Corticosteroid resistance in asthma: Cellular and molecular mechanisms

Cited by 28 publications

References 235 publications

Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells

Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells

Severe Asthma and Biologics: Managing Complex Patients

Inhaled Corticosteroids in Adults with Non-cystic Fibrosis Bronchiectasis: From Bench to Bedside. A Narrative Review

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