β2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D
Identifieur interne : 005F94 ( Main/Exploration ); précédent : 005F93; suivant : 005F95β2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D
Auteurs : Thomas Trian [Australie] ; Janette K. Burgess [Australie] ; Kyoko Niimi [Australie] ; Lyn M. Moir [Australie] ; Qi Ge [Australie] ; Patrick Berger [France] ; Stephen B. Liggett [États-Unis] ; Judith L. Black [Australie] ; Brian G. Oliver [Australie]Source :
- PLoS ONE [ 1932-6203 ] ; 2011.
Abstract
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 β-agonist induced ASM relaxation in asthmatics, but the mechanism is not known.
To characterize the potential defect in β-agonist induced cAMP in ASM derived from asthmatic in comparison to non-asthmatic subjects and to investigate its mechanism.
We examined β2-adrenergic (β2AR) receptor expression and basal β-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.
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.
Decreased β-agonist induced cAMP in ASM from asthmatics results from enhanced degradation due to increased PDE4D expression. Clinical manifestations of this dysregulation would be suboptimal β-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.
Url:
DOI: 10.1371/journal.pone.0020000
PubMed: 21611147
PubMed Central: 3096656
Affiliations:
- Australie, France, États-Unis
- Aquitaine, Maryland, Nouvelle-Aquitaine, Nouvelle-Galles du Sud
- Bordeaux, Sydney
- Université Bordeaux II, Université de Sydney
Links toward previous steps (curation, corpus...)
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- to stream Pmc, to step Checkpoint: 002118
- to stream Ncbi, to step Merge: 000A73
- to stream Ncbi, to step Curation: 000A73
- to stream Ncbi, to step Checkpoint: 000A73
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- to stream Main, to step Curation: 005F94
Le document en format XML
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Burgess</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Niimi, Kyoko" sort="Niimi, Kyoko" uniqKey="Niimi K" first="Kyoko" last="Niimi">Kyoko Niimi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Moir, Lyn M" sort="Moir, Lyn M" uniqKey="Moir L" first="Lyn M." last="Moir">Lyn M. Moir</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Ge, Qi" sort="Ge, Qi" uniqKey="Ge Q" first="Qi" last="Ge">Qi Ge</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Berger, Patrick" sort="Berger, Patrick" uniqKey="Berger P" first="Patrick" last="Berger">Patrick Berger</name><affiliation wicri:level="4"><nlm:aff id="aff3"><addr-line>Centre de Recherce Cardio-Thoracique de Bordeaux, Université Bordeaux Segalen, INSERM, Bordeaux, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre de Recherce Cardio-Thoracique de Bordeaux, Université Bordeaux Segalen, INSERM, Bordeaux</wicri:regionArea><placeName><region type="region">Nouvelle-Aquitaine</region><region type="old region">Aquitaine</region><settlement type="city">Bordeaux</settlement><settlement type="city">Bordeaux</settlement></placeName><orgName type="university">Université Bordeaux II</orgName></affiliation></author><author><name sortKey="Liggett, Stephen B" sort="Liggett, Stephen B" uniqKey="Liggett S" first="Stephen B." last="Liggett">Stephen B. Liggett</name><affiliation wicri:level="2"><nlm:aff id="aff4"><addr-line>Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Black, Judith L" sort="Black, Judith L" uniqKey="Black J" first="Judith L." last="Black">Judith L. Black</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Oliver, Brian G" sort="Oliver, Brian G" uniqKey="Oliver B" first="Brian G." last="Oliver">Brian G. Oliver</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Cell Biology, Woolcock Institute of Medical Research, Sydney, New South Wales</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff2"><addr-line>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background and Objective</title><p>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 β-agonist induced ASM relaxation in asthmatics, but the mechanism is not known.</p></sec><sec><title>Objective</title><p>To characterize the potential defect in β-agonist induced cAMP in ASM derived from asthmatic in comparison to non-asthmatic subjects and to investigate its mechanism.</p></sec><sec><title>Methods</title><p>We examined β<sub>2</sub>-adrenergic (β<sub>2</sub>AR) receptor expression and basal β-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.</p></sec><sec><title>Results</title><p>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.</p></sec><sec><title>Conclusion</title><p>Decreased β-agonist induced cAMP in ASM from asthmatics results from enhanced degradation due to increased PDE4D expression. Clinical manifestations of this dysregulation would be suboptimal β-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.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Fraser, Cm" uniqKey="Fraser C">CM Fraser</name></author><author><name sortKey="Venter, Jc" uniqKey="Venter J">JC Venter</name></author><author><name sortKey="Kaliner, M" uniqKey="Kaliner M">M Kaliner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goldie, Rg" uniqKey="Goldie R">RG Goldie</name></author><author><name sortKey="Spina, D" uniqKey="Spina D">D Spina</name></author><author><name sortKey="Henry, Pj" uniqKey="Henry P">PJ Henry</name></author><author><name sortKey="Lulich, Km" uniqKey="Lulich K">KM Lulich</name></author><author><name sortKey="Paterson, Jw" uniqKey="Paterson J">JW Paterson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deshpande, Da" 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Black</name><name sortKey="Black, Judith L" sort="Black, Judith L" uniqKey="Black J" first="Judith L." last="Black">Judith L. Black</name><name sortKey="Burgess, Janette K" sort="Burgess, Janette K" uniqKey="Burgess J" first="Janette K." last="Burgess">Janette K. Burgess</name><name sortKey="Burgess, Janette K" sort="Burgess, Janette K" uniqKey="Burgess J" first="Janette K." last="Burgess">Janette K. Burgess</name><name sortKey="Ge, Qi" sort="Ge, Qi" uniqKey="Ge Q" first="Qi" last="Ge">Qi Ge</name><name sortKey="Ge, Qi" sort="Ge, Qi" uniqKey="Ge Q" first="Qi" last="Ge">Qi Ge</name><name sortKey="Moir, Lyn M" sort="Moir, Lyn M" uniqKey="Moir L" first="Lyn M." last="Moir">Lyn M. Moir</name><name sortKey="Moir, Lyn M" sort="Moir, Lyn M" uniqKey="Moir L" first="Lyn M." last="Moir">Lyn M. Moir</name><name sortKey="Niimi, Kyoko" sort="Niimi, Kyoko" uniqKey="Niimi K" first="Kyoko" last="Niimi">Kyoko Niimi</name><name sortKey="Niimi, Kyoko" sort="Niimi, Kyoko" uniqKey="Niimi K" first="Kyoko" last="Niimi">Kyoko Niimi</name><name sortKey="Oliver, Brian G" sort="Oliver, Brian G" uniqKey="Oliver B" first="Brian G." last="Oliver">Brian G. Oliver</name><name sortKey="Oliver, Brian G" sort="Oliver, Brian G" uniqKey="Oliver B" first="Brian G." last="Oliver">Brian G. Oliver</name><name sortKey="Trian, Thomas" sort="Trian, Thomas" uniqKey="Trian T" first="Thomas" last="Trian">Thomas Trian</name></country><country name="France"><region name="Nouvelle-Aquitaine"><name sortKey="Berger, Patrick" sort="Berger, Patrick" uniqKey="Berger P" first="Patrick" last="Berger">Patrick Berger</name></region></country><country name="États-Unis"><region name="Maryland"><name sortKey="Liggett, Stephen B" sort="Liggett, Stephen B" uniqKey="Liggett S" first="Stephen B." last="Liggett">Stephen B. 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