title: Pathology of asthma.
abstract: Asthma is a serious health and socioeconomic issue all over the world, affecting more than 300 million individuals. The disease is considered as an inflammatory disease in the airway, leading to airway hyperresponsiveness, obstruction, mucus hyper-production and airway wall remodeling. The presence of airway inflammation in asthmatic patients has been found in the nineteenth century. As the information in patients with asthma increase, paradigm change in immunology and molecular biology have resulted in an extensive evaluation of inflammatory cells and mediators involved in the pathophysiology of asthma. Moreover, it is recognized that airway remodeling into detail, characterized by thickening of the airway wall, can be profound consequences on the mechanics of airway narrowing and contribute to the chronic progression of the disease. Epithelial to mesenchymal transition plays an important role in airway remodeling. These epithelial and mesenchymal cells cause persistence of the inflammatory infiltration and induce histological changes in the airway wall, increasing thickness of the basement membrane, collagen deposition and smooth muscle hypertrophy and hyperplasia. Resulting of airway inflammation, airway remodeling leads to the airway wall thickening and induces increased airway smooth muscle mass, which generate asthmatic symptoms. Asthma is classically recognized as the typical Th2 disease, with increased IgE levels and eosinophilic inflammation in the airway. Emerging Th2 cytokines modulates the airway inflammation, which induces airway remodeling. Biological agents, which have specific molecular targets for these Th2 cytokines, are available and clinical trials for asthma are ongoing. However, the relatively simple paradigm has been doubted because of the realization that strategies designed to suppress Th2 function are not effective enough for all patients in the clinical trials. In the future, it is required to understand more details for phenotypes of asthma.
authors.affiliation: Department of Clinical Immunology and Internal medicine, Graduate School of Medicine, Yokohama City University Yokohama, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kudo
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ishigatsubo
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aoki
keywords: Th17 cells; Th2 cells; Th9 cell; asthma; cytokines; epithelial to mesenchymal transition; remodeling
references.citation: N Engl J Med. 2011 Sep 22;365(12):1088-98
references.pmid: 21812663
references.citation: Am J Respir Crit Care Med. 1999 Dec;160(6):2062-6
references.pmid: 10588629
references.citation: Front Immunol. 2012 Aug 28;3:270
references.pmid: 22973272
references.citation: BMC Pulm Med. 2010 Jan 08;10:3
references.pmid: 20064211
references.citation: N Engl J Med. 2012 Mar 29;366(13):1181-9
references.pmid: 22455412
references.citation: J Allergy Clin Immunol. 1997 Jul;100(1):44-51
references.pmid: 9257786
references.citation: Eur Respir J. 2005 Jun;25(6):986-91
references.pmid: 15929952
references.citation: Nat Immunol. 2008 Dec;9(12):1341-6
references.pmid: 18931678
references.citation: Am Rev Respir Dis. 1993 Sep;148(3):713-9
references.pmid: 8368644
references.citation: Allergy. 2004 May;59(5):469-78
references.pmid: 15080825
references.citation: J Immunol. 2007 Jul 15;179(2):1080-7
references.pmid: 17617600
references.citation: N Engl J Med. 2011 May 26;364(21):2006-15
references.pmid: 21612469
references.citation: Am J Respir Cell Mol Biol. 2013 Jul;49(1):18-27
references.pmid: 23449734
references.citation: Am J Respir Cell Mol Biol. 1999 Apr;20(4):777-86
references.pmid: 10101011
references.citation: J Allergy Clin Immunol. 2000 Jan;105(1 Pt 1):108-15
references.pmid: 10629460
references.citation: Clin Exp Allergy. 2011 Mar;41(3):305-11
references.pmid: 21121984
references.citation: J Allergy Clin Immunol. 1992 May;89(5):958-67
references.pmid: 1374772
references.citation: Curr Opin Allergy Clin Immunol. 2001 Feb;1(1):47-50
references.pmid: 11964669
references.citation: J Allergy Clin Immunol. 2005 Nov;116(5):1053-7
references.pmid: 16275375
references.citation: Nat Immunol. 2011 Jun 20;12(7):597-606
references.pmid: 21685955
references.citation: J Exp Med. 2008 Feb 18;205(2):385-93
references.pmid: 18250191
references.citation: Am J Respir Crit Care Med. 2011 Nov 15;184(10):1125-32
references.pmid: 21852542
references.citation: Am J Respir Crit Care Med. 2000 May;161(5):1720-45
references.pmid: 10806180
references.citation: J Exp Med. 1994 Apr 1;179(4):1331-6
references.pmid: 8145044
references.citation: Eur Respir J. 2010 Mar;35(3):522-31
references.pmid: 19797135
references.citation: Lancet. 2007 Oct 20;370(9596):1422-31
references.pmid: 17950857
references.citation: Am J Respir Cell Mol Biol. 2004 Dec;31(6):626-32
references.pmid: 15333330
references.citation: Science. 2004 Sep 17;305(5691):1776-9
references.pmid: 15375268
references.citation: N Engl J Med. 2007 Oct 11;357(15):1487-95
references.pmid: 17928596
references.citation: Am Rev Respir Dis. 1991 Apr;143(4 Pt 1):772-7
references.pmid: 2008989
references.citation: J Allergy Clin Immunol. 2012 Feb;129(2):456-63, 463.e1-3
references.pmid: 22206777
references.citation: N Engl J Med. 2011 Feb 24;364(8):769-70
references.pmid: 21345107
references.citation: Am J Respir Cell Mol Biol. 2010 Jan;42(1):69-79
references.pmid: 19372245
references.citation: Eur Respir J. 1998 Dec;12(6):1322-6
references.pmid: 9877485
references.citation: PLoS One. 2013 May 21;8(5):e64281
references.pmid: 23700468
references.citation: J Clin Invest. 2009 Jun;119(6):1420-8
references.pmid: 19487818
references.citation: Immunity. 2010 Aug 27;33(2):192-202
references.pmid: 20674401
references.citation: Nat Med. 2012 May 04;18(5):673-83
references.pmid: 22561831
references.citation: Nat Immunol. 2005 Nov;6(11):1133-41
references.pmid: 16200068
references.citation: Am J Respir Crit Care Med. 1999 Sep;160(3):968-75
references.pmid: 10471626
references.citation: Am J Respir Cell Mol Biol. 2009 Feb;40(2):159-67
references.pmid: 18688040
references.citation: Lab Invest. 1999 Apr;79(4):395-405
references.pmid: 10211992
references.citation: Open Respir Med J. 2013;7:21-5
references.pmid: 23526476
references.citation: Nature. 2009 Jan 29;457(7229):585-8
references.pmid: 19060881
references.citation: Growth Factors. 2008 Feb;26(1):12-22
references.pmid: 18365875
references.citation: Am J Respir Cell Mol Biol. 2003 Jun;28(6):648-54
references.pmid: 12760962
references.citation: Expert Rev Clin Immunol. 2011 Jul;7(4):411-7
references.pmid: 21790283
references.citation: J Allergy Clin Immunol. 2013 May;131(5):1267-74; quiz 1275
references.pmid: 23541326
references.citation: J Clin Invest. 2012 Feb;122(2):748-58
references.pmid: 22232213
references.citation: Science. 1998 Dec 18;282(5397):2258-61
references.pmid: 9856949
references.citation: Nat Med. 2006 Sep;12(9):1023-6
references.pmid: 16906156
references.citation: N Engl J Med. 2009 Mar 5;360(10):985-93
references.pmid: 19264687
references.citation: J Clin Invest. 2012 Aug;122(8):2916-27
references.pmid: 22772469
references.citation: Infect Immun. 1998 Aug;66(8):3832-40
references.pmid: 9673269
references.citation: Mucosal Immunol. 2009 Mar;2(2):103-21
references.pmid: 19129758
references.citation: Am J Physiol. 1999 Dec;277(6):L1109-17
references.pmid: 10600880
references.citation: J Allergy. 1952 May;23(3):193-203
references.pmid: 14938011
references.citation: Chest. 2010 Nov;138(5):1140-7
references.pmid: 20538817
references.citation: Dis Chest. 1960 Dec;38:616-24
references.pmid: 13769788
references.citation: J Allergy Clin Immunol. 2010 Jun;125(6):1344-1353.e2
references.pmid: 20513525
references.citation: Lancet. 2000 Dec 23-30;356(9248):2144-8
references.pmid: 11191542
references.citation: J Immunol. 2011 Sep 15;187(6):3362-73
references.pmid: 21849676
references.citation: MMWR Morb Mortal Wkly Rep. 2011 May 6;60(17):547-52
references.pmid: 21544044
references.citation: J Allergy Clin Immunol. 2011 May;127(5):1148-54.e9
references.pmid: 21329968
references.citation: Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42
references.pmid: 16493418
references.citation: Curr Opin Allergy Clin Immunol. 2001 Feb;1(1):85-93
references.pmid: 11964675
references.citation: Am J Respir Crit Care Med. 2000 Nov;162(5):1778-82
references.pmid: 11069812
references.citation: Mucosal Immunol. 2010 Jul;3(4):399-409
references.pmid: 20336062
references.citation: Am Rev Respir Dis. 1987 Jul;136(1):225-44
references.pmid: 3605835
references.citation: J Clin Pathol. 1960 Jan;13:27-33
references.pmid: 13818688
references.citation: Am J Respir Crit Care Med. 1999 Sep;160(3):1035-42
references.pmid: 10471638
references.citation: Semin Immunol. 2011 Aug;23(4):282-92
references.pmid: 21592823
references.citation: Clin Exp Allergy. 2009 Jul;39(7):1009-17
references.pmid: 19438586
references.citation: J Immunol. 2011 Jul 1;187(1):164-71
references.pmid: 21622859
references.citation: J Immunol. 2007 Mar 1;178(5):3244-51
references.pmid: 17312173
references.citation: Am J Respir Crit Care Med. 2011 Apr 1;183(7):865-75
references.pmid: 20971830
references.citation: J Immunol. 2010 Feb 15;184(4):1663-74
references.pmid: 20130218
references.citation: Am J Respir Crit Care Med. 2011 Apr 1;183(7):834-5
references.pmid: 21471072
references.citation: J Exp Med. 2010 Sep 27;207(10):2097-111
references.pmid: 20819925
references.citation: Am J Respir Crit Care Med. 2009 Sep 1;180(5):388-95
references.pmid: 19483109
references.citation: Eur Respir J. 2006 Jan;27(1):208-29
references.pmid: 16387953
references.citation: Eur Respir J. 2009 Sep;34(3):616-28
references.pmid: 19282346
references.citation: Int Arch Allergy Immunol. 1999 Nov;120(3):218-24
references.pmid: 10592467
references.citation: Curr Mol Med. 2008 Aug;8(5):350-8
references.pmid: 18691061
references.citation: J Allergy Clin Immunol. 2004 Nov;114(5):1106-9
references.pmid: 15536417
references.citation: Thorax. 2010 Jul;65(7):626-32
references.pmid: 20627922
references.citation: Trends Mol Med. 2005 Apr;11(4):148-52
references.pmid: 15823751
references.citation: BMC Pulm Med. 2011 Feb 28;11:14
references.pmid: 21356110
references.citation: Am J Respir Crit Care Med. 2009 Apr 1;179(7):549-58
references.pmid: 19136369
references.citation: Allergy. 2012 Apr;67(4):552-9
references.pmid: 22229658
references.citation: BMJ. 1989 Nov 18;299(6710):1259-60
references.pmid: 2513902
references.citation: Lancet. 1989 Mar 11;1(8637):520-4
references.pmid: 2466184
references.citation: Clin Exp Allergy. 1994 Jan;24(1):73-80
references.pmid: 8156448
references.citation: Immunobiology. 2011 Jan-Feb;216(1-2):86-95
references.pmid: 20362352
references.citation: Clin Exp Immunol. 2002 Oct;130(1):93-100
references.pmid: 12296858
references.citation: N Engl J Med. 2002 May 30;346(22):1699-705
references.pmid: 12037149
references.citation: J Allergy Clin Immunol. 2010 Jun;125(6):1237-1244.e2
references.pmid: 20513521
references.citation: Asian Pac J Allergy Immunol. 2009 Mar;27(1):35-41
references.pmid: 19548628
references.citation: Mucosal Immunol. 2012 Mar;5(2):140-9
references.pmid: 22189956
references.citation: Allergy Asthma Clin Immunol. 2009 Oct 22;5(1):4
references.pmid: 20016776
references.citation: Clin Exp Allergy. 2000 Jun;30 Suppl 1:28-32
references.pmid: 10849471
references.citation: Eur Respir J. 1997 Feb;10(2):292-300
references.pmid: 9042623
references.citation: J Appl Physiol (1985). 2000 Apr;88(4):1413-20
references.pmid: 10749837
references.citation: J Appl Physiol (1985). 1999 Jun;86(6):2001-12
references.pmid: 10368367
references.citation: J Exp Med. 2010 Oct 25;207(11):2479-91
references.pmid: 20921287
references.citation: J Allergy Clin Immunol. 2006 Nov;118(5):1133-41
references.pmid: 17088140
references.citation: Allergy. 2007 Feb;62(2):102-12
references.pmid: 17298416
references.citation: J Allergy Clin Immunol. 2003 Jun;111(6):1319-27
references.pmid: 12789235
references.citation: Thorax. 2000 Aug;55 Suppl 1:S2-10
references.pmid: 10943631
references.citation: Clin Respir J. 2010 May;4 Suppl 1:15-9
references.pmid: 20500605
references.citation: Cell. 2006 Feb 24;124(4):783-801
references.pmid: 16497588
references.citation: J Exp Med. 2008 May 12;205(5):1063-75
references.pmid: 18411338
references.citation: Eur Respir J. 2012 Feb;39(2):439-45
references.pmid: 21828034
references.citation: Respir Med. 2000 Oct;94 Suppl F:S9-15
references.pmid: 11059962
references.citation: J Allergy Clin Immunol. 2012 Apr;129(4):974-82.e13
references.pmid: 22385633
references.citation: Clin Exp Allergy. 2006 Nov;36(11):1373-81
references.pmid: 17083347
references.citation: J Immunol. 2000 Jul 1;165(1):108-13
references.pmid: 10861042
references.citation: J Allergy Clin Immunol. 2010 Jul;126(1):133-9
references.pmid: 20538329
references.citation: Curr Opin Immunol. 2007 Dec;19(6):681-6
references.pmid: 17949963
references.citation: Thorax. 2005 Dec;60(12):1012-8
references.pmid: 16166100
references.citation: PLoS One. 2011 Jan 20;6(1):e16175
references.pmid: 21283768
references.citation: Eur Respir J. 1999 Sep;14(3):633-41
references.pmid: 10543287
references.citation: Fibrogenesis Tissue Repair. 2010 Jan 05;3(1):2
references.pmid: 20051102
references.citation: Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):896-904
references.pmid: 10988102
references.citation: Expert Rev Clin Immunol. 2010 Sep;6(5):701-4
references.pmid: 20828276
references.citation: Ann Med. 2008;40(7):482-95
references.pmid: 18608118
references.citation: Am J Pathol. 2011 Aug;179(2):603-9
references.pmid: 21708113
references.citation: J Clin Invest. 2003 Dec;112(12):1776-84
references.pmid: 14679171
references.citation: J Allergy Clin Immunol. 2000 Feb;105(2 Pt 1):193-204
references.pmid: 10669837
references.citation: N Engl J Med. 2009 Mar 5;360(10):973-84
references.pmid: 19264686
references.citation: J Clin Invest. 2003 Oct;112(7):1029-36
references.pmid: 14523040
references.citation: Clin Exp Allergy. 2008 Sep;38(9):1422-31
references.pmid: 18647314
references.citation: J Allergy Clin Immunol. 2000 Jun;105(6 Pt 1):1041-53
references.pmid: 10856134
references.citation: Immunity. 2012 Apr 20;36(4):623-34
references.pmid: 22503540
references.citation: J Clin Invest. 1999 Mar;103(6):779-88
references.pmid: 10079098
references.citation: J Exp Med. 1996 Dec 1;184(6):2429-32
references.pmid: 8976199
references.citation: Immunity. 2009 Sep 18;31(3):412-24
references.pmid: 19766084
references.citation: J Immunol. 2012 Feb 1;188(3):968-75
references.pmid: 22180613
references.citation: Pediatr Allergy Immunol. 2011 Jun;22(4):350-5
references.pmid: 21535176
references.citation: Allergy. 2006 Apr;61(4):414-21
references.pmid: 16512802
references.citation: Biochim Biophys Acta. 2009 Jun;1793(6):933-40
references.pmid: 19010359
references.citation: Am J Respir Crit Care Med. 2010 Apr 15;181(8):788-96
references.pmid: 20056900
references.citation: Chest. 2009 Apr;135(4):1045-1049
references.pmid: 19349400
references.citation: J Allergy Clin Immunol. 2009 Sep;124(3):573-82, 582.e1-9
references.pmid: 19539982
references.citation: Eur Respir J. 2000 Mar;15(3):600-16
references.pmid: 10759460
references.citation: Curr Opin Pharmacol. 2013 Jun;13(3):351-61
references.pmid: 23643194
references.citation: Allergy. 2009 Jul;64(7):995-1002
references.pmid: 19630858
references.citation: Nat Med. 2012 Mar 04;18(4):547-54
references.pmid: 22388091
references.citation: J Allergy Clin Immunol. 2003 Jun;111(6):1293-8
references.pmid: 12789232
references.citation: N Engl J Med. 2011 Feb 24;364(8):701-9
references.pmid: 21345099
references.citation: Am J Respir Crit Care Med. 1999 Sep;160(3):1001-8
references.pmid: 10471631
references.citation: Am J Respir Crit Care Med. 2007 Jul 15;176(2):121-8
references.pmid: 17379851
references.citation: Allergy. 2006 May;61(5):589-97
references.pmid: 16629789
references.citation: J Immunol. 2010 Jul 15;185(2):834-41
references.pmid: 20530256
references.citation: J Allergy Clin Immunol. 2009 May;123(5):986-94; quiz 995-6
references.pmid: 19410688
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Jan;278(1):L193-201
references.pmid: 10645907
references.citation: Nat Immunol. 2011 Oct 12;12(12):1159-66
references.pmid: 21993848
references.citation: Am J Respir Crit Care Med. 2008 Oct 1;178(7):667-72
references.pmid: 18565953
references.citation: J Allergy Clin Immunol. 2011 Sep;128(3):549-56.e1-12
references.pmid: 21752437
references.citation: Eur Respir J. 2009 Nov;34(5):1040-5
references.pmid: 19282340
references.citation: Am J Respir Crit Care Med. 2009 Jul 15;180(2):122-33
references.pmid: 19406982
references.citation: Eur Respir J. 2008 Jul;32(1):61-9
references.pmid: 18321931
references.citation: J Allergy Clin Immunol. 2008 Aug;122(2):335-41, 341.e1-3
references.pmid: 18572228
references.citation: J Clin Immunol. 2013 Apr;33(3):595-604
references.pmid: 23180361
references.citation: Curr Drug Targets Inflamm Allergy. 2005 Aug;4(4):415-23
references.pmid: 16101518
references.citation: FASEB J. 2000 Jul;14(10):1362-74
references.pmid: 10877829
references.citation: Thorax. 1968 Mar;23(2):168-72
references.pmid: 4172544
references.citation: J Allergy Clin Immunol. 2010 Jan;125(1):222-30.e1-4
references.pmid: 20109749
references.citation: Sci Transl Med. 2010 Oct 6;2(52):52ra72
references.pmid: 20926833
references.citation: Am J Respir Crit Care Med. 2010 Jun 1;181(11):1200-6
references.pmid: 20167852
references.citation: N Engl J Med. 1992 Jan 30;326(5):298-304
references.pmid: 1530827
references.citation: Am Rev Respir Dis. 1993 Nov;148(5):1220-5
references.pmid: 8239157
references.citation: Allergy Asthma Immunol Res. 2012 Mar;4(2):68-79
references.pmid: 22379601
references.citation: Am J Respir Cell Mol Biol. 1990 Nov;3(5):507-11
references.pmid: 2223105
references.citation: Thorax. 1998 Apr;53(4):248-53
references.pmid: 9741365
references.citation: J Exp Med. 2005 Mar 21;201(6):937-47
references.pmid: 15781584
references.citation: Respir Physiol. 1999 Oct 15;118(1):1-13
references.pmid: 10568415
references.citation: J Allergy Clin Immunol. 2013 Feb;131(2):562-70
references.pmid: 23174657
references.citation: J Allergy Clin Immunol. 1998 Mar;101(3):386-90
references.pmid: 9525456
references.citation: J Allergy Clin Immunol. 2007 Nov;120(5):997-1009; quiz 1010-1
references.pmid: 17681364
references.citation: Nat Immunol. 2005 Nov;6(11):1123-32
references.pmid: 16200070
references.citation: Allergy Asthma Proc. 1998 Nov-Dec;19(6):353-8
references.pmid: 9876774
references.citation: Clin Exp Allergy. 1999 Jun;29 Suppl 2:90-5
references.pmid: 10421830
references.citation: Clin Exp Allergy. 2001 Jun;31(6):934-42
references.pmid: 11422160