title: Mechanism of glucocorticoid protection of airway smooth muscle from proasthmatic effects of long-acting beta2-adrenoceptor agonist exposure.
abstract: BACKGROUND
  Chronic use of long-acting beta2-adrenergic receptor agonists (LABAs), resulting in beta2-adrenergic receptor desensitization, has been associated with increased asthma morbidity. When LABAs are used in combination with inhaled glucocorticoids, however, asthma control is improved, raising the following question: Do glucocorticoids inhibit the proasthmatic mechanism that mediates altered contractility in LABA-exposed airway smooth muscle (ASM)?
  
  
  OBJECTIVE
  This study aimed to identify the potential protective role and mechanism of action of glucocorticoids in mitigating the effects of prolonged LABA exposure on ASM constrictor and relaxation responsiveness.
  
  
  METHODS
  Cultured human ASM cells and isolated rabbit ASM tissues were examined for induced changes in agonist-mediated cyclic adenosine monophosphate accumulation, constrictor and relaxation responsiveness, and expression of specific glucocorticoid-regulated molecules after 24-hour exposure to the LABA salmeterol in the absence and presence of dexamethasone.
  
  
  RESULTS
  Salmeterol-exposed ASM exhibited impaired cyclic adenosine monophosphate and relaxation responses to isoproterenol and increased acetylcholine-induced contractility. These proasthmatic effects of prolonged LABA exposure were attributed to upregulated phosphodiesterase 4 (PDE4) activity and were ablated by pretreatment with dexamethasone. Further studies demonstrated that (1) dexamethasone suppressed activation of the mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2), which upregulate PDE4 expression in salmeterol-exposed ASM; and (2) the inhibitory actions of dexamethasone on salmeterol-induced ERK1/2 activation and resultant PDE4-mediated changes in ASM responsiveness were prevented by gene silencing or pharmacologic inhibition of dexamethasone-induced expression of mitogen-activated protein kinase phosphatase 1, an endogenous deactivator of ERK1/2 signaling.
  
  
  CONCLUSIONS
  Glucocorticoids prevent the adverse proasthmatic effects of prolonged LABA exposure on airway responsiveness as a result of glucocorticoid-induced upregulation of mitogen-activated protein kinase phosphatase 1, which inhibits proasthmatic ERK1/2 signaling in the LABA-exposed ASM.
authors.affiliation: Children's Hospital of Philadelphia Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Nino
authors.forename: Aihua
authors.initials: A
authors.lastname: Hu
authors.forename: Judith S
authors.initials: JS
authors.lastname: Grunstein
authors.forename: Michael M
authors.initials: MM
authors.lastname: Grunstein
mesh_terms: D000318:Adrenergic beta-Agonists / Q000009:adverse effects*; D000420:Albuterol / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D001249:Asthma / Q000517:prevention & control*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009130:Muscle, Smooth / Q000187:drug effects*; D011817:Rabbits; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000068299:Salmeterol Xinafoate; D015854:Up-Regulation
chemical_list: D000318:Adrenergic beta-Agonists; D005938:Glucocorticoids; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D048052:Mitogen-Activated Protein Kinase 3; D054638:Dual Specificity Phosphatase 1; D000420:Albuterol
references.citation: Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):996-1001
references.pmid: 10712354
references.citation: N Engl J Med. 1992 Oct 22;327(17):1198-203
references.pmid: 1357550
references.citation: Eur Respir J. 2006 Jun;27(6):1286-306
references.pmid: 16772391
references.citation: J Immunol. 2004 Jun 1;172(11):7053-9
references.pmid: 15153527
references.citation: Am J Respir Cell Mol Biol. 2001 Dec;25(6):761-71
references.pmid: 11726403
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Sep;291(3):L324-33
references.pmid: 16581829
references.citation: Am J Respir Cell Mol Biol. 2008 Jan;38(1):1-7
references.pmid: 17673687
references.citation: Life Sci. 2006 Oct 26;79(22):2077-85
references.pmid: 16875702
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1055-67
references.pmid: 18359889
references.citation: J Allergy Clin Immunol. 2005 Jul;116(1):94-101
references.pmid: 15990780
references.citation: EMBO J. 2001 Dec 17;20(24):7108-16
references.pmid: 11742987
references.citation: Clin Sci (Lond). 1998 Jun;94(6):557-72
references.pmid: 9854452
references.citation: Ann Intern Med. 2008 Jul 1;149(1):33-42
references.pmid: 18523132
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L746-57
references.pmid: 19666775
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6751-6
references.pmid: 10841571
references.citation: J Biol Chem. 1996 Oct 25;271(43):27018-24
references.pmid: 8900190
references.citation: J Immunol. 2007 Jun 1;178(11):7366-75
references.pmid: 17513787
references.citation: Am J Respir Cell Mol Biol. 1998 Aug;19(2):338-48
references.pmid: 9698608
references.citation: Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 3):S201-6
references.pmid: 9817746
references.citation: Respir Physiol Neurobiol. 2003 Sep 16;137(2-3):179-95
references.pmid: 14516725
references.citation: J Allergy Clin Immunol. 1999 Aug;104(2 Pt 2):S18-30
references.pmid: 10452785
references.citation: J Cell Physiol. 2008 Sep;216(3):673-9
references.pmid: 18338817
references.citation: Am J Respir Crit Care Med. 1996 May;153(5):1481-8
references.pmid: 8630590
references.citation: Am J Respir Crit Care Med. 2005 Apr 15;171(8):823-8
references.pmid: 15665325
references.citation: J Allergy Clin Immunol. 2005 Aug;116(2):292-8
references.pmid: 16083782
references.citation: Br J Pharmacol. 2008 Mar;153(6):1090-104
references.pmid: 18071293
references.citation: J Biol Chem. 2000 Aug 25;275(34):26615-24
references.pmid: 10851231
references.citation: Eur J Pharmacol. 2007 Oct 1;571(2-3):215-21
references.pmid: 17610865
references.citation: J Allergy Clin Immunol. 2008 Oct;122(4):734-740
references.pmid: 18774166
references.citation: Br J Pharmacol. 2002 Feb;135(4):987-96
references.pmid: 11861327
references.citation: Am J Respir Crit Care Med. 2001 Jan;163(1):173-84
references.pmid: 11208644
references.citation: Biochem Soc Trans. 2003 Dec;31(Pt 6):1186-90
references.pmid: 14641023
references.citation: J Allergy Clin Immunol. 2009 Jan;123(1):249-57
references.pmid: 19130938
references.citation: Br J Pharmacol. 1997 Aug;121(8):1523-30
references.pmid: 9283684
references.citation: Mol Cell Biol. 1993 Sep;13(9):5195-205
references.pmid: 8355678
references.citation: Chest. 2006 Jan;129(1):15-26
references.pmid: 16424409
references.citation: Proc Am Thorac Soc. 2004;1(3):231-4
references.pmid: 16113439
references.citation: N Engl J Med. 1997 Nov 13;337(20):1405-11
references.pmid: 9358137
references.citation: Biochem Soc Trans. 2006 Dec;34(Pt 6):1018-23
references.pmid: 17073741
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L186-93
references.pmid: 18441094
references.citation: FASEB J. 2003 Oct;17(13):1831-41
references.pmid: 14519662
references.citation: Cochrane Database Syst Rev. 2009 Jul 08;(3):CD007949
references.pmid: 19588447