title: Mechanisms of airway hyper-responsiveness in asthma: the past, present and yet to come.
abstract: Airway hyper-responsiveness (AHR) has long been considered a cardinal feature of asthma. The development of the measurement of AHR 40 years ago initiated many important contributions to our understanding of asthma and other airway diseases. However, our understanding of AHR in asthma remains complicated by the multitude of potential underlying mechanisms which in reality are likely to have different contributions amongst individual patients. Therefore, the present review will discuss the current state of understanding of the major mechanisms proposed to contribute to AHR and highlight the way in which AHR testing is beginning to highlight distinct abnormalities associated with clinically relevant patient populations. In doing so we aim to provide a foundation by which future research can begin to ascribe certain mechanisms to specific patterns of bronchoconstriction and subsequently match phenotypes of bronchoconstriction with clinical phenotypes. We believe that this approach is not only within our grasp but will lead to improved mechanistic understanding of asthma phenotypes and we hoped to better inform the development of phenotype-targeted therapy.
authors: Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Medicine, University of Vermont College of Medicine, Burlington, VT, USA.
authors: D G
authors: DG
authors: Chapman
authors: C G
authors: CG
authors: Irvin
mesh_terms: D001249:Asthma / Q000175:diagnosis* / Q000209:etiology*; D006801:Humans; D010641:Phenotype; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000175:diagnosis* / Q000209:etiology*
references: J Immunol. 2009 Oct 1;183(7):4682-92
references: 19734226
references: Am J Respir Crit Care Med. 1996 Feb;153(2):582-9
references: 8564102
references: Expert Rev Respir Med. 2012 Jun;6(3):321-9
references: 22788946
references: Respirology. 2006 Jan;11(1):54-61
references: 16423202
references: J Appl Physiol (1985). 2007 Jan;102(1):399-405
references: 16946028
references: Thorax. 1983 Nov;38(11):854-8
references: 6648868
references: Am J Respir Crit Care Med. 2001 Oct 15;164(8 Pt 1):1376-81
references: 11704581
references: Thorax. 2002 Apr;57(4):309-16
references: 11923548
references: Pulm Pharmacol Ther. 2013 Feb;26(1):42-9
references: 22939888
references: Am Rev Respir Dis. 1991 Feb;143(2):441-3
references: 1990965
references: Respir Med. 2014 Aug;108(8):1091-9
references: 24958604
references: Allergy. 2012 Apr;67(4):552-9
references: 22229658
references: Am J Physiol Lung Cell Mol Physiol. 2002 Dec;283(6):L1181-9
references: 12388349
references: Thorax. 2005 May;60(5):395-400
references: 15860715
references: Respir Med. 2008 Feb;102(2):256-65
references: 17964770
references: Clin Allergy. 1977 Nov;7(6):503-13
references: 589783
references: Eur Respir J. 2000 Aug;16(2):226-35
references: 10968496
references: Am J Respir Cell Mol Biol. 2000 Dec;23(6):794-802
references: 11104733
references: J Appl Physiol (1985). 2015 Mar 15;118(6):692-8
references: 25571989
references: J Asthma. 2011 May;48(4):345-50
references: 21504349
references: Eur Respir J. 2009 Jun;33(6):1396-402
references: 19196811
references: Am J Physiol. 1997 Sep;273(3 Pt 1):L648-55
references: 9316501
references: Am J Respir Crit Care Med. 1994 Nov;150(5 Pt 2):S63-71
references: 7952596
references: Respirology. 2014 Aug;19(6):852-6
references: 24975800
references: J Appl Physiol (1985). 1993 Jun;74(6):2771-81
references: 8365980
references: Am J Respir Crit Care Med. 2008 Aug 1;178(3):218-24
references: 18480428
references: J Allergy Clin Immunol. 2012 Mar;129(3 Suppl):S65-87
references: 22386510
references: Clin Allergy. 1977 May;7(3):235-43
references: 908121
references: Clin Exp Allergy. 2014 Oct;44(10):1240-5
references: 24912796
references: Respirology. 2013 Oct;18(7):1128-34
references: 23734667
references: Br J Clin Pharmacol. 1986 Dec;22(6):669-76
references: 2882770
references: Respir Med. 2011 Apr;105(4):533-40
references: 21050738
references: Am J Respir Crit Care Med. 1999 Jul;160(1):336-41
references: 10390421
references: Nature. 1981 Mar 26;290(5804):343-4
references: 6111025
references: Arch Intern Med. 1965 Apr;115:452-8
references: 14272372
references: Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1318-22
references: 11029338
references: Thorax. 1983 Oct;38(10):760-5
references: 6648855
references: Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1043-51
references: 10194144
references: Chest. 2003 Jul;124(1):63-9
references: 12853503
references: Respir Physiol Neurobiol. 2011 Dec 15;179(2-3):269-75
references: 21939788
references: J Appl Physiol (1985). 1985 Feb;58(2):326-38
references: 3838543
references: Am J Respir Crit Care Med. 2002 Feb 1;165(3):327-31
references: 11818315
references: J Allergy Clin Immunol. 2005 May;115(5):897-909; quiz 910
references: 15867841
references: Am J Respir Crit Care Med. 1999 May;159(5 Pt 1):1574-9
references: 10228129
references: N Engl J Med. 2003 Oct 9;349(15):1414-22
references: 14534334
references: Am J Respir Crit Care Med. 2001 Feb;163(2):406-12
references: 11179114
references: Nature. 2005 Apr 7;434(7034):777-82
references: 15772676
references: Am J Physiol Lung Cell Mol Physiol. 2011 Jan;300(1):L121-31
references: 20971805
references: Am J Respir Crit Care Med. 2003 Oct 15;168(8):983-8
references: 12829452
references: J Appl Physiol (1985). 1990 Dec;69(6):2209-14
references: 2077018
references: J Allergy Clin Immunol. 1983 Apr;71(4):399-406
references: 6601124
references: Respir Physiol Neurobiol. 2010 Sep 30;173(2):157-63
references: 20688195
references: Am J Respir Crit Care Med. 2007 Apr 1;175(7):661-6
references: 17234901
references: Am J Respir Crit Care Med. 2007 Apr 15;175(8):768-74
references: 17255559
references: Pulm Pharmacol. 1988;1(1):25-31
references: 2980284
references: J Allergy Clin Immunol. 2012 Jul;130(1):69-75.e6
references: 22465214
references: Am Rev Respir Dis. 1987 Aug;136(2):379-83
references: 3304046
references: J Appl Physiol Respir Environ Exerc Physiol. 1977 Dec;43(6):1054-62
references: 606690
references: Respirology. 2014 Oct;19(7):1046-51
references: 24995907
references: Clin Exp Allergy. 2009 Dec;39(12):1815-21
references: 20085597
references: J Appl Physiol (1985). 2003 Jul;95(1):426-34
references: 12794101
references: Ann Allergy Asthma Immunol. 2013 Sep;111(3):182-4
references: 23987192
references: Am J Respir Crit Care Med. 2014 Jun 15;189(12):1494-502
references: 24821412
references: Br J Pharmacol. 1989 Mar;96(3):688-92
references: 2720298
references: Ann Allergy Asthma Immunol. 2014 Apr;112(4):354-60.e1
references: 24507830
references: Eur Respir J. 1994 May;7(5):881-7
references: 8050544
references: FASEB J. 1988 Jul;2(10):2605-8
references: 3384240
references: J Asthma. 2008 Mar;45(2):109-13
references: 18350401
references: Respirology. 2014 Nov;19(8):1170-7
references: 25138203
references: Chest. 2001 Jun;119(6):1685-90
references: 11399691
references: J Allergy Clin Immunol. 2008 Aug;122(2):335-41, 341.e1-3
references: 18572228
references: Am J Respir Crit Care Med. 1995 Sep;152(3):865-71
references: 7663797
references: J Appl Physiol (1985). 2012 Feb;112(4):627-37
references: 22114176
references: Eur Respir J. 2001 Aug;18(2):272-8
references: 11529284
references: Respir Res. 2009;10:4
references: 19161635
references: J Allergy Clin Immunol. 2010 Nov;126(5):952-8
references: 20934208
references: Am J Respir Cell Mol Biol. 1997 Aug;17(2):144-6
references: 9271301
references: Eur Respir J. 2006 Mar;27(3):495-503
references: 16507848
references: Am J Respir Cell Mol Biol. 2009 Jan;40(1):13-8
references: 18617678
references: Am J Respir Crit Care Med. 2010 Feb 15;181(4):315-23
references: 19892860
references: Pharmacol Ther. 2009 Apr;122(1):19-29
references: 19141302
references: Lancet. 2009 Nov 21;374(9703):1754-64
references: 19932356
references: Am J Respir Crit Care Med. 2009 Feb 1;179(3):194-204
references: 19011151
references: Am Rev Respir Dis. 1990 Mar;141(3):589-94
references: 2178525
references: Thorax. 2007 Aug;62(8):684-9
references: 17311839
references: J Allergy Clin Immunol. 2004 Mar;113(3):496-502
references: 15007353
references: N Engl J Med. 2002 May 30;346(22):1699-705
references: 12037149
references: Proc Am Thorac Soc. 2009 May 1;6(3):306-11
references: 19387035
references: Clin Exp Allergy. 2008 Jan;38(1):43-50
references: 18028458
references: J Appl Physiol (1985). 2012 Sep;113(6):958-66
references: 22837168
references: J Appl Physiol (1985). 2002 Aug;93(2):705-13
references: 12133882
references: N Engl J Med. 2011 May 26;364(21):2006-15
references: 21612469
references: Clin Exp Allergy. 1997 Apr;27(4):363-71
references: 9146928
references: Respir Med. 2005 Aug;99(8):1046-52
references: 15950147
references: Am Rev Respir Dis. 1986 Oct;134(4):812-5
references: 2945504
references: J Allergy Clin Immunol. 2008 May;121(5):1196-202
references: 18405955
references: Am J Respir Cell Mol Biol. 2015 Mar;52(3):304-14
references: 25055045
references: Clin Exp Allergy. 2015 Jan;45(1):21-31
references: 24766371
references: Eur Respir J. 2013 Dec;42(6):1503-12
references: 23722612
references: J Allergy Clin Immunol. 2013 Apr;131(4):1008-16
references: 23419540
references: BMJ. 2000 Mar 25;320(7238):827-32
references: 10731173
references: Am J Physiol. 1996 Jun;270(6 Pt 1):L1040-51
references: 8764231
references: J Allergy Clin Immunol. 1989 May;83(5):855-61
references: 2654253
references: Chest. 1992 Aug;102(2):347-55
references: 1643912
references: Eur J Hum Genet. 2000 Nov;8(11):853-60
references: 11093275
references: Eur Respir J. 2008 Dec;32(6):1563-9
references: 18653648
references: Chest. 2008 Oct;134(4):678-80
references: 18842907
references: Thorax. 1988 Apr;43(4):300-5
references: 2970125
references: Am J Respir Crit Care Med. 2012 May 15;185(10):1058-64
references: 22403800
references: Respir Med. 1995 May;89(5):351-6
references: 7638370
references: Am Rev Respir Dis. 1992 May;145(5):1087-91
references: 1375009
references: Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L378-85
references: 18178673
references: Am J Respir Crit Care Med. 1999 Mar;159(3):911-6
references: 10051272
references: Eur Respir J. 2012 Jul;40(1):45-54
references: 22267756
references: Eur Respir J. 1999 Feb;13(2):295-300
references: 10065671
references: Allergy. 2014 Sep;69(9):1233-40
references: 24888725
references: Front Physiol. 2012 Dec 10;3:460
references: 23233839
references: J Appl Physiol (1985). 2011 May;110(5):1241-7
references: 21393472
references: J Allergy Clin Immunol. 2011 Sep;128(3):508-15.e1-2
references: 21782230
references: Ann Am Thorac Soc. 2015 Mar;12(3):357-63
references: 25575246
references: J Appl Physiol (1985). 2013 May 15;114(10):1460-71
references: 23493364
references: J Allergy Clin Immunol. 1982 Sep;70(3):170-7
references: 7108068
references: Chest. 2012 Mar;141(3):607-15
references: 21998259
references: Am J Respir Cell Mol Biol. 2011 Oct;45(4):746-52
references: 21297080
references: Thorax. 2006 Aug;61(8):671-7
references: 16670173
references: J Appl Physiol (1985). 2004 Jun;96(6):2019-27
references: 14660507
references: Am J Respir Crit Care Med. 2012 Feb 1;185(3):267-74
references: 22108207
references: Chest. 2011 Jun;139(6):1395-401
references: 21454398
references: Environ Mol Mutagen. 2014 Apr;55(3):244-55
references: 24446183
references: PLoS One. 2014;9(2):e90565
references: 24587395
references: J Asthma. 2015 Feb;52(1):26-33
references: 25019351
references: Ned Tijdschr Geneeskd. 1962 Nov 10;106:2295-6
references: 13998028
references: Eur Respir J. 2003 Jun;21(6):1046-9
references: 12797502