b2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D

Trian, T; Burgess, JK; Niimi, K; Moir, LM; Ge, Q; Berger, P; Liggett, SB; Black, JL; Oliver, BG

b2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D

Trian, T Burgess, JK Niimi, K Moir, LM Ge, Q Berger, P Liggett, SB Black, JL Oliver, BG

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Publisher:: Public library of Science
Publication Type:: Journal Article
Citation:: PLoS One, 2011, 6 (5)
Issue Date:: 2011-01

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Field	Value	Language
dc.contributor.author	Trian, T	en_US
dc.contributor.author	Burgess, JK	en_US
dc.contributor.author	Niimi, K	en_US
dc.contributor.author	Moir, LM	en_US
dc.contributor.author	Ge, Q	en_US
dc.contributor.author	Berger, P	en_US
dc.contributor.author	Liggett, SB	en_US
dc.contributor.author	Black, JL	en_US
dc.contributor.author	Oliver, BG	en_US
dc.date.issued	2011-01	en_US
dc.identifier.citation	PLoS One, 2011, 6 (5)	en_US
dc.identifier.issn	1932-6203	en_US
dc.identifier.uri	http://hdl.handle.net/10453/29758
dc.description.abstract	Background and Objective: Asthma is associated with airway narrowing in response to bronchoconstricting stimuli and increased airway smooth muscle (ASM) mass. In addition, some studies have suggested impaired b-agonist induced ASM relaxation in asthmatics, but the mechanism is not known. Objective: To characterize the potential defect in b-agonist induced cAMP in ASM derived from asthmatic in comparison to non-asthmatic subjects and to investigate its mechanism. Methods: We examined b2-adrenergic (b2AR) receptor expression and basal b-agonist and forskolin (direct activator of adenylyl cyclase) stimulated cAMP production in asthmatic cultured ASM (n = 15) and non-asthmatic ASM (n = 22). Based on these results, PDE activity, PDE4D expression and cell proliferation were determined. Results: In the presence of IBMX, a pan PDE inhibitor, asthmatic ASM had ,50% lower cAMP production in response to isoproterenol, albuterol, formoterol, and forskolin compared to non-asthmatic ASM. However when PDE4 was specifically inhibited, cAMP production by the agonists and forskolin was normalized in asthmatic ASM. We then measured the amount and activity of PDE4, and found ,2-fold greater expression and activity in asthmatic ASM compared to non-asthmatic ASM. Furthermore, inhibition of PDE4 reduced asthmatic ASM proliferation but not that of non-asthmatic ASM. Conclusion: Decreased b-agonist induced cAMP in ASM from asthmatics results from enhanced degradation due to increased PDE4D expression. Clinical manifestations of this dysregulation would be suboptimal b-agonist-mediated bronchodilation and possibly reduced control over increasing ASM mass. These phenotypes appear to be ``hard-wired into ASM from asthmatics, as they do not require an inflammatory environment in culture to be observed.	en_US
dc.publisher	Public library of Science	en_US
dc.relation.ispartof	PLoS One	en_US
dc.relation.isbasedon	10.1371/journal.pone.0020000	en_US
dc.subject.classification	General Science & Technology	en_US
dc.title	b2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D	en_US
dc.type	Journal Article
utslib.citation.volume	5	en_US
utslib.citation.volume	6	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	MD Multidisciplinary	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.declined	1970-01-01T00:00:00.0+1000
pubs.consider-herdc	false	en_US
pubs.deleted	1970-01-01T00:00:00.0+1000
pubs.issue	5	en_US
pubs.volume	6	en_US

Abstract:

Background and Objective: Asthma is associated with airway narrowing in response to bronchoconstricting stimuli and increased airway smooth muscle (ASM) mass. In addition, some studies have suggested impaired b-agonist induced ASM relaxation in asthmatics, but the mechanism is not known. Objective: To characterize the potential defect in b-agonist induced cAMP in ASM derived from asthmatic in comparison to non-asthmatic subjects and to investigate its mechanism. Methods: We examined b2-adrenergic (b2AR) receptor expression and basal b-agonist and forskolin (direct activator of adenylyl cyclase) stimulated cAMP production in asthmatic cultured ASM (n = 15) and non-asthmatic ASM (n = 22). Based on these results, PDE activity, PDE4D expression and cell proliferation were determined. Results: In the presence of IBMX, a pan PDE inhibitor, asthmatic ASM had ,50% lower cAMP production in response to isoproterenol, albuterol, formoterol, and forskolin compared to non-asthmatic ASM. However when PDE4 was specifically inhibited, cAMP production by the agonists and forskolin was normalized in asthmatic ASM. We then measured the amount and activity of PDE4, and found ,2-fold greater expression and activity in asthmatic ASM compared to non-asthmatic ASM. Furthermore, inhibition of PDE4 reduced asthmatic ASM proliferation but not that of non-asthmatic ASM. Conclusion: Decreased b-agonist induced cAMP in ASM from asthmatics results from enhanced degradation due to increased PDE4D expression. Clinical manifestations of this dysregulation would be suboptimal b-agonist-mediated bronchodilation and possibly reduced control over increasing ASM mass. These phenotypes appear to be ``hard-wired into ASM from asthmatics, as they do not require an inflammatory environment in culture to be observed.

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http://hdl.handle.net/10453/29758