Mechanism of glucocorticoid protection of airway smooth muscle from proasthmatic effects of long-acting β2-adrenoceptor agonist exposure Gustavo Nino,

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Presentation transcript:

Mechanism of glucocorticoid protection of airway smooth muscle from proasthmatic effects of long-acting β2-adrenoceptor agonist exposure Gustavo Nino, MD, Aihua Hu, MD, PhD, Judith S. Grunstein, MA, Michael M. Grunstein, MD, PhD Journal of Allergy and Clinical Immunology Volume 125, Issue 5, Pages 1020-1027 (May 2010) DOI: 10.1016/j.jaci.2010.02.007 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Dexamethasone (DEX) prevents impaired acute ß2AR-induced cAMP accumulation in salmeterol-exposed HASM cells. In contrast with control cells, acute isoproterenol (ISO)–induced cAMP accumulation is suppressed in HASM cells pre-exposed for 24 hours to salmeterol. By comparison, ISO-induced cAMP accumulation is preserved in salmeterol-exposed HASM cells that are cotreated with DEX. Data represent means ± SEs from 4 paired experiments. ∗∗P < .01 compared with untreated cells by using the paired t test. Journal of Allergy and Clinical Immunology 2010 125, 1020-1027DOI: (10.1016/j.jaci.2010.02.007) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Dexamethasone (DEX) prevents salmeterol (SAL)–induced changes in agonist responsiveness in rabbit ASM tissues. Relative to controls, ASM tissues exposed to SAL exhibit significantly increased contractility to acetylcholine (ACh;A) and impaired relaxation to isoproterenol (B). Pretreatment with either rolipram or DEX prevents the SAL-induced changes in ASM responsiveness. Data represent means ± SEs from 6 to 7 experiments. ANOVA used for multiple comparisons of mean Tmax values. Journal of Allergy and Clinical Immunology 2010 125, 1020-1027DOI: (10.1016/j.jaci.2010.02.007) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Dexamethasone (DEX) prevents ß2AR agonist-induced upregulation of PDE4 in HASM cells. Relative to untreated controls, PDE4D5 mRNA expression (A) and cAMP PDE activity (B) are upregulated in HASM cells exposed to either salmeterol or isoproterenol. ß2AR agonist–induced upregulation of PDE4D5 transcripts and PDE activity is abrogated in cells pretreated with DEX. Data are means ± SEs from 5 experiments. ∗∗P < .01 compared with untreated cells by using the paired t test. Journal of Allergy and Clinical Immunology 2010 125, 1020-1027DOI: (10.1016/j.jaci.2010.02.007) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 A, HASM cells exposed to either salmeterol or isoproterenol exhibit increased ERK1/2 phosphorylation that is prevented by pretreating the ß2AR agonist-exposed cells with dexamethasone (DEX). B, Corresponding densitometric analysis demonstrates similar increases in ERK1/2 phosphorylation (p-ERK1/2) in salmeterol-exposed and isoproterenol-exposed cells that are prevented by pretreatment with DEX. Data are means ± SEs from 4 determinations under each treatment condition. ∗P <.05 compared with untreated cells by using the paired t test. Journal of Allergy and Clinical Immunology 2010 125, 1020-1027DOI: (10.1016/j.jaci.2010.02.007) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 A, Dexamethasone (DEX)–induced upregulation of MKP-1 protein is prevented in HASM cells transfected with MKP-1 siRNA duplexes. DEX-induced suppression of upregulated ERK1/2 phosphorylation (B) and PDE4D5 mRNA (C) expression in salmeterol-exposed cells is abrogated by transfection with MKP-1 siRNAs, whereas transfection with scRNA (negative control) has no effect. D, DEX-induced suppression of upregulated PDE activity in salmeterol-exposed cells is prevented by transfection with the MKP-1 siRNAs or by pretreatment with Ro-31-8220. Data are means ± SEs from 5 experiments. ∗∗P < .01 compared with untreated cells by using the paired t test. Journal of Allergy and Clinical Immunology 2010 125, 1020-1027DOI: (10.1016/j.jaci.2010.02.007) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 MKP-1 siRNA prevents dexamethasone (DEX)–induced suppression of the proasthmatic effects of salmeterol (SAL) on ASM responsiveness. Rabbit ASM tissues exposed to salmeterol exhibit significantly increased contractility to acetylcholine (ACh;A) and impaired relaxation responses to isoproterenol (B) that are prevented by pretreatment with DEX. The protective effects of DEX are abrogated in SAL-exposed tissues transfected with MKP-1 siRNAs. Data are means ± SEs from 5 to 7 paired experiments. ANOVA used for multiple comparisons of mean Tmax values. Journal of Allergy and Clinical Immunology 2010 125, 1020-1027DOI: (10.1016/j.jaci.2010.02.007) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions