Effects of budesonide and formoterol on allergen-induced airway responses, inflammation, and airway remodeling in asthma

Kelly, Margaret M.; O’Connor, Terence M.; Leigh, Richard; Otis, Joceline; Gwozd, Carol; Gauvreau, Gail M.; Gauldie, Jack; O'Byrne, Paul M.

doi:10.1016/j.jaci.2009.09.011

Cited by 109 publications

(121 citation statements)

References 61 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…Our observation that a β 2 -adrenergic receptor agonist inhibits ASMC migration to a variety 14 of stimuli raises the possibility that the use of β 2 -adrenergic receptor agonists may help to attenuate some aspects of remodeling in asthma. This would be consistent with a recent study showing that combination therapy with an inhaled corticosteroid and long-acting β 2 -adrenergic receptor agonist, but not an inhaled corticosteroid alone, inhibited antigen induced alterations in airway smooth muscle and myofibroblast numbers in asthmatic subjects (32).…”

Section: Hrv-induced Asmc Migration Is Mediated At Least In Part VIsupporting

confidence: 92%

Human Rhinovirus Infection of Epithelial Cells Modulates Airway Smooth Muscle Migration

Shariff

Shelfoon

Holden

et al. 2017

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Rationale: Airway remodeling, a characteristic feature of asthma, begins in early life. Recurrent human rhinovirus (HRV) infections are a potential inciting stimulus for remodeling. One component of airway remodeling is an increase in airway smooth muscle cell mass with a greater proximity of the airway smooth muscle cells (ASMC) to the airway epithelium. We asked whether human bronchial epithelial cells infected with HRV produced mediators that are chemotactic for ASMC.Methods: ASMC migration was investigated using the modified Boyden Chamber and the xCELLigence Real-Time Cell Analyzer. Multiplex bead analysis was used to measure HRVinduced epithelial chemokine release. The chemotactic effects of CCL5, CXCL8 and CXCL10 were also examined.Results: Supernatants from HRV-infected epithelial cells caused ASMC chemotaxis. Pretreatment of ASMC with pertussis toxin abrogated chemotaxis, as did treatment with formoterol, forskolin, or 8-bromo-cAMP. CCL5, CXCL8, and CXCL10 were most up-regulated chemokines produced by HRV-infected airway epithelial cells. When recombinant CCL5, CXCL8 and CXCL10 were used at levels found in epithelial supernatants they induced ASMC chemotaxis similar to that seen with epithelial cell supernatants. When examined individually, CCL5 was the most effective chemokine in causing ASMC migration and treatment of supernatant from HRVinfected epithelial cells with anti-CCL5 antibodies significantly attenuated ASMC migration. Conclusion:These findings suggest that HRV-induced CCL5 can induce ASMC chemotaxis, and thus may contribute to the pathogenesis of airway remodeling in asthmatic patients.3

show abstract

Section: Hrv-induced Asmc Migration Is Mediated At Least In Part VIsupporting

confidence: 92%

Human Rhinovirus Infection of Epithelial Cells Modulates Airway Smooth Muscle Migration

Shariff

Shelfoon

Holden

et al. 2017

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, in humans, loss of bronchoprotection from regularly administered b 2 -agonists seems to reverse only with acute high doses of ICS [27,28] and it is not clear that this happens with chronic use of ICS at low or medium doses [29][30][31]. Recent findings suggest that the mechanism by which ICS plus LABA therapy exerts its synergistic beneficial effects is through an increased antiinflammatory activity and an attenuation of airway remodelling [32]. Additionally, despite a post hoc finding and high number of missing values in this variable, an increased risk of BHR among carriers of the Arg allele and no interaction with ICS use suggest that BHR may occur through persistent activation of b 2 -AR by LABAs.…”

Section: Discussionmentioning

confidence: 99%

ADRB2Gly16Arg polymorphism, asthma control and lung function decline

Rebordosa¹,

Kogevinas

Guerra

et al. 2011

Eur Respir J

View full text Add to dashboard Cite

Arg/Arg homozygotes for the Gly16Arg polymorphism in the b 2 -adrenoreceptor gene (ADRB2) have a reduced response to short-acting b 2 -agonists but no effect has been associated with long-acting b 2 -agonists (LABAs).We selected 604 subjects with current asthma from the European Community Respiratory Health Study to evaluate whether asthma control and lung function decline were associated with Gly16Arg polymorphism, and to test whether LABA or inhaled corticosteroid (ICS) use modified these effects.There was an increased risk of noncontrolled asthma (OR 1.33, 95% CI 1.01-1.75; p50.046) for each Arg allele. Among nonusers of ICS, the odds ratio of noncontrolled asthma among Arg/Arg versus Gly/Gly subjects was 2.73 (95% CI 1.28-5.82; p50.009). No increased risk of noncontrolled asthma associated with the Arg allele was observed among ICS and/or LABA users. For each Arg allele, a mean¡SE decrease in decline in forced expiratory volume in 1 s of 7.7¡2.5 mL?yr -1 was found (p-value for trend 0.003), irrespective of ICS or LABA use. Arg/Arg subjects had an increased risk of bronchial hyperresponsiveness (BHR) versus Gly/Gly subjects, with an odds ratio of 2.51 (95% CI 1.12-5.63; p50.025) if they did not use ICS. The Arg allele was associated with poorer asthma control, a steeper lung function decline and BHR. Absence of genotypic effects on asthma control among ICS users may be due to reversed b 2 -adrenoreceptor desensitisation.

show abstract

“…Thus increase in ASM mass occurs unimpeded in asthmatic subjects irrespective of how effectively asthma symptoms are managed. In addition to their lack of effect in vivo, both corticosteroids and ␤-agonists have limited efficacy in inhibiting ASM proliferation by relevant mitogens in cell-based assays (5,6,10,18,21,28,30,47,55). Our previous studies have demonstrated that protein kinase A (PKA) plays a central role in mediating the functional effects of ␤-agonists on ASM (37, 39, 55).…”

mentioning

confidence: 99%

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Sharma

Panebra

Pera

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

-Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediateconductance calcium-activated K ϩ channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as bronchoconstriction in obstructive airway disease. asthma; airway remodeling; G protein-coupled receptor; type 2 taste receptors G PROTEIN-COUPLED RECEPTOR (GPCR) signaling plays a vital role in the regulation of airway smooth muscle (ASM) contraction, relaxation, and proliferation (4, 12). Exaggerated presentation of procontractile GPCR agonists in the airways during allergic inflammation contributes to bronchoconstriction in obstructive airway disease such as asthma. Another salient feature of inflammatory airway diseases is airway remodeling that is characterized by excessive proliferation and accumulation of resident cells, including ASM cells. Animal models demonstrate ASM mass is increased by allergic airway inflammation, while human studies demonstrate a progressive increase in ASM mass in asthmatic subjects that increases both dynamic and fixed airway resistance, limiting the effectiveness of current rescue bronchodilators (11,21,22,26). Current antiasthma therapies, including ␤-agonists and corticosteroids, aim at alleviating bronchoconstriction and infl...

show abstract

Effects of budesonide and formoterol on allergen-induced airway responses, inflammation, and airway remodeling in asthma

Cited by 109 publications

References 61 publications

Human Rhinovirus Infection of Epithelial Cells Modulates Airway Smooth Muscle Migration

Human Rhinovirus Infection of Epithelial Cells Modulates Airway Smooth Muscle Migration

ADRB2Gly16Arg polymorphism, asthma control and lung function decline

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Contact Info

Product

Resources

About