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

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Presentation transcript:

Salmeterol attenuates chemotactic responses in rhinovirus-induced exacerbation of allergic airways disease by modulating protein phosphatase 2A Luke Hatchwell, BBiomedSci (Hons), Jason Girkin, BBiomedSci (Hons), Matthew D. Dun, PhD, Matthew Morten, BBiomedSci (Hons), Nicole Verrills, PhD, Hamish D. Toop, BSci (Hons), Jonathan C. Morris, PhD, Sebastian L. Johnston, PhD, Paul S. Foster, PhD, DSc, Adam Collison, PhD, Joerg Mattes, MD, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 6, Pages 1720-1727 (June 2014) DOI: 10.1016/j.jaci.2013.11.014 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Salmeterol suppresses AHR and inflammation in AAD. A, Total lung resistance (RI) presented as raw baseline values and percentage change in response to methacholine (n = 8 mice per group). B, Cells in bronchoalveolar lavage (BAL) fluid. C, Tissue eosinophils per 100 μm2. D, Proportions of blood leukocytes. Results are presented as means ± SEMs (n = 3-6 mice per group). *P < .05 and **P < .01 compared with the vehicle control group. Eos, Eosinophils; Lym, lymphocytes; Mac, macrophages; Neu, neutrophils; SAL, sterile saline. Journal of Allergy and Clinical Immunology 2014 133, 1720-1727DOI: (10.1016/j.jaci.2013.11.014) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Salmeterol attenuates chemokine but not TH2 cytokine expression. A and B, Cytokine/chemokine expression in lower airway tissue (Fig 2, A and B) and protein levels of CXCL2 (Fig 2, B). C-E, PP2A activity (Fig 2, C), p-ERK1 (Fig 2, D), and activated NF-κB subunits (Fig 2, E) quantified from lung lysates by using ELISA. Results are presented as means ± SEMs (n = 3-6 mice per group). *P < .05, **P < .01, and ***P < .001 compared with the vehicle control group. SAL, Sterile saline. Journal of Allergy and Clinical Immunology 2014 133, 1720-1727DOI: (10.1016/j.jaci.2013.11.014) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Inhibition of PP2A reverses the therapeutic effect of salmeterol. A and B, PP2A activity and PP2Ac protein (Fig 3, A) and chemokines (Fig 3, B) in lung lysates. C, Cells in bronchoalveolar lavage (BAL) fluid. Eos, Eosinophils; Lym, lymphocytes; Mac, macrophages; Neu, neutrophils. D, Cytokine expression in lower airway tissue. Results are presented as means ± SEMs (n = 3-6 mice per group). *P < .05, **P < .01, and ***P < .001 compared with the vehicle control group or otherwise indicated. SAL, Sterile saline. Journal of Allergy and Clinical Immunology 2014 133, 1720-1727DOI: (10.1016/j.jaci.2013.11.014) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Salmeterol and dexamethasone suppress rhinovirus-induced exacerbation. A, Total lung resistance (RI) presented as raw baseline values and percentage change in response to methacholine (n = 6-9 mice per group). B, Tissue eosinophils per 100 μm2. C and D, Gene expression in lower airway tissue (Fig 4, C and D) and protein levels of CCL20 and CXCL2 (Fig 4, D). Results are presented as means ± SEMs (n = 3-6 mice per group). *P < .05 and **P < .01 compared with the vehicle control group. SAL, Sterile saline. Journal of Allergy and Clinical Immunology 2014 133, 1720-1727DOI: (10.1016/j.jaci.2013.11.014) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Salmeterol, but not dexamethasone, increases PP2A activity in vivo and in vitro. PP2A activity in lung lysates of rhinovirus-exacerbated mice (A), human BEAS-2B cells (B), or immunopurified PP2A complexes (C) after treatment with salmeterol, dexamethasone, or their combination is shown. Results are presented as means ± SEMs (n = 4-6 mice per group or 3 independent experiments). *P < .05, **P < .01, and ***P < .001 compared with the vehicle control group. SAL, Sterile saline. Journal of Allergy and Clinical Immunology 2014 133, 1720-1727DOI: (10.1016/j.jaci.2013.11.014) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 The PP2A agonist AAL(S) prevents rhinovirus-induced exacerbation. A and B, PP2A activity (Fig 6, A) and total lung resistance (RI; Fig 6, B) are presented as raw baseline values and percentage change in response to methacholine (n = 4-6 mice per group). C and D, Tissue eosinophils per 100 μm2 (Fig 6, C) and gene and protein expression of chemokines (Fig 6, D). Results are presented as means ± SEMs (n = 3-5 mice per group). *P < .05 and ***P < .001 compared with the vehicle control group. Journal of Allergy and Clinical Immunology 2014 133, 1720-1727DOI: (10.1016/j.jaci.2013.11.014) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions