title: Emerging targets for novel therapy of asthma.
abstract: Significant advances in understanding the cell and molecular biology of inflammation and airway smooth muscle (ASM) contractility have identified several potential novel targets for therapies of asthma. New agents targeting G-protein coupled receptors (GPCRs) including bitter taste receptors (TAS2R) agonists and prostaglandin EP4 receptor agonists elicit ASM relaxation. The cAMP/PKA pathway continues to be a promising drug target with the emergence of new PDE inhibitors and a novel PKA target protein, HSP20, which mediates smooth muscle relaxation via actin depolymerization. Smooth muscle relaxation can also be elicited by inhibitors of the RhoA/Rho kinase pathway via inhibition of myosin light chain phosphorylation and actin depolymerization. Targeting epigenetic processes that control chromatin remodeling and RNA-induced gene silencing in airway cells also holds great potential for novel asthma therapy. Further investigation may identify agents that inhibit smooth muscle contraction and/or restrain or reverse obstructive remodeling of the airways.
authors: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL 36688, USA. wgerthoffer@southalabama.edu
authors: William T
authors: WT
authors: Gerthoffer
authors: Julian
authors: J
authors: Solway
authors: Blanca
authors: B
authors: Camoretti-Mercado
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D050886:HSP20 Heat-Shock Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D043562:Receptors, G-Protein-Coupled; D058309:Receptors, Prostaglandin E, EP4 Subtype; C568609:TAS2R1 protein, human; D054460:rho-Associated Kinases; D006655:Histone Deacetylases
references: Curr Allergy Asthma Rep. 2009 Nov;9(6):475-83
references: 19814921
references: J Physiol. 2000 May 1;524 Pt 3:865-78
references: 10790164
references: Nat Med. 2012 May 04;18(5):648-50; author reply 650-1
references: 22561814
references: J Allergy Clin Immunol. 2011 Jul;128(1):160-167.e4
references: 21571357
references: J Biol Chem. 2010 Sep 17;285(38):29336-47
references: 20525681
references: J Biol Chem. 1997 Apr 25;272(17):11283-7
references: 9111032
references: J Allergy Clin Immunol. 2010 Oct;126(4):754-762.e1
references: 20920765
references: Discov Med. 2011 Apr;11(59):283-91
references: 21524382
references: Nat Med. 2010 Nov;16(11):1299-304
references: 20972434
references: J Biol Chem. 1999 Apr 16;274(16):11344-51
references: 10196226
references: Am J Physiol Lung Cell Mol Physiol. 2012 Sep;303(5):L460-8
references: 22773691
references: Pulm Pharmacol Ther. 2013 Feb;26(1):64-74
references: 22634303
references: Thorax. 1999 Oct;54(10):900-4
references: 10491452
references: Expert Rev Respir Med. 2012 Jun;6(3):309-19
references: 22788945
references: Clin Exp Allergy. 2005 Jan;35(1):89-96
references: 15649272
references: Cell Health Cytoskelet. 2009 Jun 1;2009(1):27-42
references: 21686039
references: Am J Respir Cell Mol Biol. 2011 Nov;45(5):1069-74
references: 21642585
references: J Pharmacol Exp Ther. 2007 Feb;320(2):766-73
references: 17105828
references: Mini Rev Med Chem. 2006 Mar;6(3):339-48
references: 16515473
references: Eur J Pharmacol. 2006 Dec 15;552(1-3):135-42
references: 17026989
references: PPAR Res. 2012;2012:809164
references: 22966222
references: J Asthma. 2012 Mar;49(2):121-8
references: 22233225
references: Proc Am Thorac Soc. 2009 May 1;6(3):295-300
references: 19387033
references: Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L214-9
references: 18487358
references: Pharmacol Ther. 2008 Jul;119(1):44-54
references: 18579210
references: Curr Opin Pharmacol. 2012 Jun;12(3):238-45
references: 22445544
references: FASEB J. 2005 Feb;19(2):261-3
references: 15598710
references: Pulm Pharmacol Ther. 2013 Feb;26(1):112-20
references: 22634112
references: Clin Exp Allergy. 2006 Feb;36(2):183-91
references: 16433855
references: Thorax. 2011 Dec;66(12):1029-35
references: 21606476
references: Thorax. 2002 Jun;57(6):524-7
references: 12037228
references: J Immunol. 2012 Jul 15;189(2):819-31
references: 22689881
references: J Allergy Clin Immunol. 2007 Feb;119(2):328-35
references: 17141851
references: Am J Respir Crit Care Med. 2009 Oct 15;180(8):713-9
references: 19644046
references: Am J Respir Cell Mol Biol. 2012 Feb;46(2):132-8
references: 22298527
references: Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L984-91
references: 19717551
references: Exp Toxicol Pathol. 2008 Jun;60(1):9-15
references: 18434112
references: Am J Respir Cell Mol Biol. 2006 Dec;35(6):722-9
references: 16858009
references: Ther Adv Respir Dis. 2009 Oct;3(5):235-43
references: 19812111
references: Am J Respir Cell Mol Biol. 2010 Apr;42(4):506-13
references: 19541842
references: Am J Physiol Lung Cell Mol Physiol. 2008 Jan;294(1):L69-78
references: 17993590
references: J Pharmacol Sci. 2010;114(3):264-8
references: 20953121
references: Pulm Pharmacol Ther. 2012 Feb;25(1):115-8
references: 22244823
references: Am J Respir Cell Mol Biol. 2013 Mar;48(3):346-53
references: 23239497
references: Respir Res. 2011 Jan 13;12:8
references: 21232113
references: Jpn J Physiol. 2005 Dec;55(6):373-8
references: 16417677
references: Am J Physiol Lung Cell Mol Physiol. 2012 Aug 15;303(4):L304-11
references: 22683571