"Role for β2ar biased signaling to address the β-agonist controversy in asthma"
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1 "Role for β2ar biased signaling to address the β-agonist controversy in asthma" Julia K. L. Walker, Ph.D. Professor in Duke University School of Nursing and Pulmonary Medicine Support provided by NHLBI & NIAID: R01HL084123, R01HL093103, R01AI079236, 1R01-AI110007
2 New perspectives on the β-agonist Outline controversy in asthma Asthma: signs and symptoms Beta-2-adrenergic receptors (β2ar) and β-agonists The β-agonist controversy Results from animal models Dual signalling pathways of β2ar New therapeutic opportunities
3 Dual β 2 AR Signaling Pathways β-agonist βarrestin β2ar Gs AC MAPK camp??? reduced Ca ++ Dickey, Walker, Hanania, Bond. COPhar 10(3): 254-9, 2010 Promote inflammation & AHR Reduce ASM contraction
4 Asthma Review
5 Asthma is a chronic inflammatory disorder Influx of inflammatory cells (Th2 & Eos) Increased mucin production and secretion Airway remodeling Airway hyperresponsiveness (twitchy) Reversible airway obstruction Cough, wheeze, shortness of breath
6 Picture of asthma attack airway Jeffery,P.K., Am. J. Respir. Crit. Care Med., 164: S28-S38, 2001
7 FEV1 and Methacholine PC 20 FEV1: forced expired volume in 1 second PC 20 methacholine: Airway hyperresponsiveness indicator Baseline FEV1 is measured Inhale aerosolized escalating doses of MCh, measure FEV1 MCh dose at which FEV1 has declined 20% from baseline The more hyperresponsive a patient is, the lower the PC 20
8 Murine Asthma Model Methods & Measurements OVA = ovalbumin
9 Airway hyperresponsiveness predicts asthma severity and future risk in humans.
10 The Controversy Surrounding β 2 AR agonist use in Asthma Review β 2 AR
11 β 2- adrenergic receptor (β 2 AR) NH 2 EXTRACELLULAR INTRACELLULAR COOH ~ 200 functionally known receptors ~ 600 functionally unassigned receptors (orphan) Hundreds of sensory (taste and smell) and hormone receptors Targets for ~ 40% of all prescription drugs
12 βarrestin proteins The Arrestin Family Name Length % Identity Expression -arrestin AA 100 Ubiquitous -arrestin AA 95 Ubiquitous Arrestin 404 AA 66 Retina R1 A P A SB/H R2
13 β 2- adrenergic receptor (β 2 AR)
14 GRK / -arrestin Mediate Desensitization Classic Paradigm of 7TMR Signaling of Seven Trans-Membrane Receptors Shenoy & Lefkowiz, Science, 2005
15 GRK New / -arrestin Paradigm Mediate of -Arrestin Desensitization function: -Arrestin of Seven Trans-Membrane Acts as a Signaling Receptors Molecule Shenoy & Lefkowiz, Science, 2005
16 7TMR Signal Transduction NEW PARADIGM NEWER PARADIGM Shenoy & Lefkowiz, Science, 2005
17 β2ar-mediated bronchodilation Figure credit to themedicalbiochemistrypage.org
18 The Controversy Surrounding β 2 AR use in Asthma
19 β-agonist treatment in asthma: SABAs and LABAs Short Acting Beta Agonists (SABAs) used for immediate relief of bronchospasm Rapid onset of action, but short duration albuterol ie., ventolin, bricanyl Long Acting Beta Agonists (LABAs) ~ 12 h effect Inhaled twice daily (in combination with ICS) Bronchodilation BPE reduces bronchoconstriction Salmeterol (Advair) & Formoterol (Symbicort)
20 Deleterious Effects of Chronic Inhaled ß2- agonist use in Asthmatics (Short-acting) Epidemic of asthma deaths followed introduction of: high-dose isoproterenol in the UK, 1960s fenoterol in New Zealand, late 1970s Regular use of short-acting inhaled ß2-agonists: increases airway responsiveness to allergen increases asthma morbidity reduces effectiveness of rescue ß2-agonist Short-acting ß2-agonist for RESCUE ONLY
21 Controversy surrounding LABA use concerns about mortality risk Salmeterol Nationwide Surveillance Study (1993) Salmeterol Multicenter Asthma Research Trial (2003) functional β2ar tachyphylaxis (Newnham et al., 1994; 1995; Grove and Lipworth, 1995), deterioration of asthma control (Sears, 2002; Salpeter et al.,2006) death (Stolley and Schinnar, 1978; Spitzer et al., 1992; Pearce et al., 1995). no adverse events of chronic beta-agonism (Drazen et al., 1996; Dennis et al., 2000; Bateman et al., 2008)
22 Controversy Surrounding LABA use in Asthma Results of FDA randomized, double-blind, controlled clinical trials - LABA + ICS avoids adverse asthma events Stempel et al., 2016 NEJM vol 374:pg 1822 Stempel et al., 2016 NEJM vol 375:pg 840 The four studies supported the decision to remove the Boxed WARNING retain a Warning and Precaution related to the increased risk of asthma-related death when LABAs are used without an ICS to treat asthma.
23 Nature, Nov. 4, 2004 To say a drug may not kill you if you take enough of a second drug is hardly a ringing endorsement for the first drug. - Richard Bond
24 Dual β 2 AR Signaling Pathways β-agonist βarrestin β2ar Gs AC MAPK camp??? reduced Ca ++ Dickey, Walker, Hanania, Bond. COPhar 10(3): 254-9, 2010 Promote inflammation & AHR Reduce ASM contraction
25 Does β 2 AR Activation Drive the Asthma Phenotype?
26 Does β 2 AR Activation Drive the Asthma Phenotype? 1. Genetic deletion of β 2 AR: effect on asthma phenotype β 2 AR-KO mice
27 β2-ar gene disruption reduces airway inflammation Nguyen L P et al. PNAS 2009;106:
28 β2-ar gene disruption reduces mucin content in the airway epithelium. Nguyen L P et al. PNAS 2009;106:
29 β2-ar gene disruption reduces airway hyperresponsiveness WT-OVA WT-alum WT-OVA β2ar-ko-ova Nguyen L P et al. PNAS 2009;106:
30 Does β 2 AR Activation Drive the Asthma Phenotype? Summary of murine data 1. Mice that lack β2ar do not develop the asthma phenotype
31 Does β 2 AR Activation Drive the Asthma Phenotype? 2. Genetic epinephrine deletion: effect on asthma phenotype PNMT-KO mice
32 Loss of endogenous epinephrine prevents airway inflammation Thanawala et al. AJRCMB 48(2): , 2013
33 Loss of endogenous epinephrine prevents elevated airway mucin volume Thanawala et al. AJRCMB 48(2): , 2013
34 Loss of endogenous epinephrine prevents airway hyperresponsiveness Thanawala et al. AJRCMB 48(2): , 2013
35 Does β 2 AR Activation Drive the Asthma Phenotype? Summary of murine data 1. Mice that lack β2ar do not develop the asthma phenotype 2. Mice that lack epinephrine do not develop the asthma phenotype
36 Does β 2 AR Activation Drive the Asthma Phenotype? 3. Exogenous Administration of β2ar-agonist: effect on asthma phenotype Chronic Salbutamol Treatment
37 Chronic administration of albuterol: effect on asthma phenotype 10 g ova, i.p. Chronic OVA +/- Albuterol Treatment Ova Aerosol Inhalation + Oropharyngeal Albuterol AHR Day 0 Day 14 Day 21,23,25 Day 28,30,32 Day 35,37,39 Day 42,44,46 Day 49,51,53 Day 56,58,60 Day 61 Lavage and Histology mucin and airway inflammation Lin et al., BJP (2012):
38 Chronic albuterol treatment promotes airway inflammation and mucin production Lin et al., BJP (2012): Airway Inflammation Alum-Saline OVA-Saline OVA-Albuterol * PAS Score Alum-Saline OVA-Saline OVA-Albuterol * 0 0 Alum-Saline OVA-Saline OVA-Albuterol
39 Chronic albuterol treatment promotes airway hyperresponsiveness 200 Alum-Saline * APTI (cm H 2 O x sec) OVA-Saline OVA-Albuterol * 0 Lin et al, BJP 2012,
40 Does β 2 AR Activation Drive the Asthma Phenotype? YES! (at least in mice) Summary of murine data 1. Mice that lack β2ar do not develop the asthma phenotype 2. Mice that lack epinephrine do not develop the asthma phenotype 3. Mice chronically treated with albuterol display a more severe asthma phenotype
41 β2ar Dual Signaling Pathways
42 Dual β2ar Signaling Paradigm β 2 AR-KO βarr2-ko βarrestin β-agonist + Epinephrine-KO Gs AC MAPK??? camp reduced Ca ++ Pro-inflammatory Pro-asthmatic Relief from Bronchospasm Dickey, Walker, Hanania, Bond. COPhar 10(3): , 2010
43 Does β-arrestin-dependent signaling drive the asthma phenotype?
44 Wild-type WT alum arr2-ko alum WT OVA arr2-ko OVA -arrestin-2-ko Walker et al., JCI, 2003
45 Cell Differentials and Lavage Cytokines in OVA-treated WT and -arrestin-2-ko mice A arr2 ** WT-ova- KO-ova- ** pg/ml 9 6 ** 40 pg/ml IL-4 IL-5 IL-13 0 Lavage total cells, lymphocytes, eosinophils and TH2- cytokines were significantly elevated in OVA-treated WT mice but not -arrestin-2-ko mice Walker et al., JCI, 2003
46 Is βarr2 required for Perpetuation of the Asthma Phenotype? Asthma Resolution Study
47 Asthma Resolution Study Chen et al., AJRCMB 2015
48 Asthma Resolution Study Results for whole lung are shown here TMX treatment significantly reduces βarr2 expression. Chen et al., AJRCMB 2015
49 Asthma Resolution Study OVA-induced airway responsiveness to MCh requires βarr2 expression Chen et al., AJRCMB 2015
50 Asthma Resolution Study βarr2 expression plays a role in OVA-induced lung inflammation. Chen et al., AJRCMB 2015
51 Asthma Resolution Study βarr2 expression may/may not play a role in OVAinduced airway inflammation and mucin production. Chen et al., AJRCMB 2015
52 Does βarr-dependent signaling drive the Asthma Phenotype? Summary of murine data 1. Mice that lack βarr2 do not develop the asthma phenotype despite being sensitized to OVA 2. Mice that have an established asthma phenotype lose AHR when βarr2 expression is significantly reduced βarr2 mediates both the development and the perpetuation of the asthma phenotype*
53 Does the β2ar-mediated β-arrestin-dependent signaling pathway drive the asthma phenotype?
54 Dual β2ar Signaling Paradigm β 2 AR-KO βarr2-ko βarrestin β-agonist + Epinephrine-KO Gs AC MAPK??? camp reduced Ca ++ Pro-inflammatory Pro-asthmatic Relief from Bronchospasm Dickey, Walker, Hanania, Bond. COPhar 10(3): , 2010
55 Does the β2ar-mediated βarr2 dependent signaling pathway drive the asthma phenotype? What Cell Types? Airway Epithelial Cells? Airway Smooth Muscle Cells? TH2 cells?
56 Does the β2ar-mediated βarr2 dependent signaling pathway drive the asthma phenotype? What Cell Types? Airway Epithelial Cells? Airway Smooth Muscle Cells? TH2 cells?
57 What Cell Types? Airway Epithelial Cells? PLOS ONE DOI: /journal.pone July 10, 2015
58 What Cell Types? Airway Epithelial Cells? Epinephrine-mediated activation of β2ar (and not β1ar) is required for IL-13 induced Mucin production in NHBE cells Al-Sawahla et al PLOS ONE July 10, 2015
59 What Cell Types? Airway Epithelial Cells? β2ar activates ERK ½ signaling in NHBE. This activation is inhibited by FR Al-Sawahla et al PLOS ONE July 10, 2015
60 Does the β2ar-mediated βarr2 dependent signaling pathway drive the asthma phenotype? What Cell Types? Airway Epithelial Cells? Airway Smooth Muscle Cells? TH2 cells?
61 arr2 constrains 2 -AR signal transduction in Airway Smooth Muscle Johnson; Am.J.Resp.Crit.Care Med., 1998
62 βarrestin-2 constrains β2ar-mediated camp accumulation in human ASMCs A B 30 ISO Culture: 1 sirna: CON arr-1/2 βarr-1 βarr-2 1 M ISO-stimulated camp (pmol/well) CON ARR sirna * -actin time (min) Human Cell Culture Data βarrestins are expressed in human trachealis. βarrestins functionally constrain Iso-induced camp accumulation in human ASM cells. Deshpande et al., FASEB J, 2008.
63 βarrestin-2 constrains β2ar-induced in vivo airway relaxation 0 % change in airway response * WT-Albuterol WT-PGE 2-50 arr2-ko-albuterol arr2-ko-pge 2 In vivo Data βarrestin-2 functionally constrains β 2 AR- mediated, but not PGE 2 -mediated, ASM relaxation. Deshpande et al., FASEB J, 2008.
64 Biasing β 2 AR Signaling Pathways β 2 AR-KO βarr2-ko βarrestin β-agonist + Epinephrine-KO Gs AC MAPK??? camp reduced Ca ++ Pro-inflammatory Pro-asthmatic Relief from Bronchospasm Dickey, Walker, Hanania, Bond. COPhar 10(3): , 2010
65 What are biased ligands?
66 Receptor Theory for Dual β 2 AR Signaling Pathways Walker et al., British Journal of Pharmacology (2011)
67 Most (known) β2ar agonists are not biased allosteric modulation? G-biased βarrestin-biased Rajagopal, Ahn, Lefkowitz, 2011, Mol Pharm, 80:367
68 Genetic Polymorphisms of β2ar Ortega et al., 2015,8:9-22 Ortega Bleecker 2007,27:665 ACUTE SABA - Arg/Arg bronchodilation CHRONIC SABA Arg/Arg deterioration symptoms
69 Genetic Variants in β2ar Arg16 homozygotes (more common in Asians) showed increased bronchodilation to SABA (acutely), but loss of bronchodilatory effect when SABA administered chronically multiple clinical retrospective and prospective clinical trials were not able to identify significant differences in PEFRresponsiveness to LABA therapy between Gly16Arg genotypes. 4 th TM domain - (Thr 164 Ile) reduced SABA and LABA affinity, decreased Gs signaling (more common in non-hispanic whites) Ortega 2015,8:9-22
70 Pharmacogenetic Genes for β2ar effect Common in Puerto Ricans and Mexicans SABA response; effect on LABA? Ortega et al., 2015,8:9-22
71 Genetic Polymorphisms of β2ar 2015,8:9-22 Asthma: complex pathophysiology; Symptom heterogeneity; Influenced by gene-gene and geneenvironment interactions Precision Medicine? Genetic profiles must: therapeutic responsiveness, adverse responses, gene-gene interactions (LABA + ICS), drug metabolism, consider severity subgroups and appropriateness of response.
72 Walker Lab Akhil Hegde, Ph.D. Joelle Romac, M.S. Barbara Theriot, B.S. Yeon ho Choi, Ph.D. Acknowledgements Thomas Jefferson University Ray Penn, PhD Deepak Deshpande, PhD Duke University Bob Lefkowitz, M.D. Wei Chen, PhD University of Houston Richard Bond, Ph.D. Brian Knoll, PhD Burton Dickey, M.D. Support provided by NHLBI & NIAID: R01HL084123, R01HL093103, R01AI079236, 1R01-AI110007
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