Salmeterol attenuates chemotactic responses in rhinovirus-induced exacerbation of allergic airways disease聽by modulating protein phosphatase 2A

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• 作者：Luke Hatchwell ; BBiomedSci (Hons)^a ; ^b ; Jason Girkin ; BBiomedSci (Hons)^a ; ^b ; Matthew D. Dun ; PhD^c ; ^d ; Matthew Morten ; BBiomedSci (Hons)^a ; ^b ; Nicole Verrills ; PhD^c ; ^d ; Hamish D. Toop ; BSci (Hons)^e ; Jonathan C. Morris ; PhD^e ; Sebastian L. Johnston ; PhD^f ; Paul S. Foster ; PhD ; DSc^b ; Adam Collison ; PhD^a ; ^b ; Joerg Mattes ; MD ; PhD^a ; ^b ; ^g ; ^{Joerg.Mattes@newcastle.edu.au" class="auth_mail}
• 关键词：Long-acting 尾2-agonist ; salmeterol ; formoterol ; salbutamol ; asthma ; allergy ; rhinovirus ; exacerbation ; chemokine ; dexamethasone ; (S)-2-amino-4-(4-[heptyloxy]phenyl)-2-methylbutan-1-ol ; protein phosphatase 2A ; nuclear factor 魏B
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：June 2014
• 年：2014
• 卷：133
• 期：6
• 页码：1720-1727
• 全文大小：1156 K

文摘

尾-Agonists are used for relief and control of asthma symptoms by reversing bronchoconstriction. They might also have anti-inflammatory properties, but the underpinning mechanisms remain poorly understood. Recently, a direct interaction between formoterol and protein phosphatase 2A (PP2A) has been described in vitro.

c_2">Objective

We sought to elucidate the molecular mechanisms by which 尾-agonists exert anti-inflammatory effects in allergen-driven and rhinovirus 1B–exacerbated allergic airways disease (AAD).

c_3">Methods

Mice were sensitized and then challenged with house dust mite to induce AAD while receiving treatment with salmeterol, formoterol, or salbutamol. Mice were also infected with rhinovirus 1B to exacerbate lung inflammation and therapeutically administered salmeterol, dexamethasone, or the PP2A-activating drug (S)-2-amino-4-(4-[heptyloxy]phenyl)-2-methylbutan-1-ol (AAL[S]).

c_4">Results

Systemic or intranasal administration of salmeterol protected against the development of allergen- and rhinovirus-induced airway hyperreactivity and decreased eosinophil recruitment to the lungs as effectively as dexamethasone. Formoterol and salbutamol also showed anti-inflammatory properties. Salmeterol, but not dexamethasone, increased PP2A activity, which reduced CCL11, CCL20, and CXCL2 expression and reduced levels of phosphorylated extracellular signal-regulated kinase 1 and active nuclear factor 魏B subunits in the lungs. The anti-inflammatory effect of salmeterol was blocked by targeting the catalytic subunit of PP2A with small RNA interference. Conversely, increasing PP2A activity with AAL(S) abolished rhinovirus-induced airway hyperreactivity, eosinophil influx, and CCL11, CCL20, and CXCL2 expression. Salmeterol also directly activated immunoprecipitated PP2A in vitro isolated from human airway epithelial cells.

c_5">Conclusions

Salmeterol exerts anti-inflammatory effects by increasing PP2A activity in AAD and rhinovirus-induced lung inflammation, which might potentially account for some of its clinical benefits.