Airway remodeling in asthma: what really matters

Heinz Fehrenbach, Christina Wagner, Michael Wegmann, Heinz Fehrenbach, Christina Wagner, Michael Wegmann

Abstract

Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and "endotyped" human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

Keywords: Airway pathology; Airway remodeling; Asthma.

Figures

Fig. 1
Fig. 1
Fraction of epithelial basal membrane (BM) of human endobronchial biopsies exhibiting complete denudation is inversely correlated with biopsy volume (=size), which was estimated according to the Cavalieri Principle. Figure by courtesy of Dr. V.A. Bratu, modified from Bratu (2008); Fig. 3.4c
Fig. 2
Fig. 2
Intra-epithelial eosinophilic granulocyte (arrowhead) in main bronchus of a murine lung chronically challenged with ovalbumin according to the protocol of Wegmann et al. (2005). Tissue was fixed with 4% paraformaldehyde, embedded into glycol methacrylate and the section was Congo Red-stained for eosinophils. AE airway epithelium. Black arrows indicate eosinophilic granulocytes in subepithelial interstitial tissue
Fig. 3
Fig. 3
Transmission electron micrograph of a cross-section through a terminal airway branch derived from the respiratory tract of Drosophila melanogaster, 3rd instar larva. Tissue was processed as described elsewhere (Fehrenbach et al. 1987). Ultrathin sections were cut on an Ultracut E microtome, collected on formvar-coated nickel grids, stained with lead citrate and analyzed using a Zeiss EM 900. AS airway space; BL basal lamina; Cu cuticula; Ep epithelium; Nu nucleus and MC muscle cells. Black arrowheads indicate a cellular junction

References

    1. Abram M, Wegmann M, Fokuhl V, et al. Nerve growth factor and neurotrophin-3 mediate survival of pulmonary plasma cells during the allergic airway inflammation. J Immunol. 2009;182:4705–12. doi: 10.4049/jimmunol.0802814.
    1. Acharya KR, Ackerman SJ. Eosinophil granule proteins: form and function. J Biol Chem. 2014;289:17406–15. doi: 10.1074/jbc.R113.546218.
    1. Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and endotypes. Allergy. 2012;67:835–46. doi: 10.1111/j.1398-9995.2012.02832.x.
    1. Al-Muhsen S, Johnson JR, Hamid Q. Remodeling in asthma. J Allergy Clin Immunol. 2011;128:451–462. doi: 10.1016/j.jaci.2011.04.047.
    1. Al-Ramli W, Préfontaine D, Chouiali F, et al. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 2009;123:1185–7. doi: 10.1016/j.jaci.2009.02.024.
    1. An SS, Bai TR, Black JL, et al. Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma. Eur Respir J. 2007;29:834–860. doi: 10.1183/09031936.00112606.
    1. Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med. 2013;19:548–56. doi: 10.1038/nm.3160.
    1. Atherton HC, Jones G, Danahay H. IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation. Am J Physiol Lung Cell Mol Physiol. 2003;285:L730–9. doi: 10.1152/ajplung.00089.2003.
    1. Avdalovic MV, Putney LF, Schelegle ES, et al. Vascular remodeling is airway generation-specific in a primate model of chronic asthma. Am J Respir Crit Care Med. 2006;174:1069–76. doi: 10.1164/rccm.200506-848OC.
    1. Bai TR. Evidence for airway remodeling in chronic asthma. Curr Opin Allergy Clin Immunol. 2010;10:82–6. doi: 10.1097/ACI.0b013e32833363b2.
    1. Bai TR, Knight DA. Structural changes in the airways in asthma: observations and consequences. Clin Sci (Lond) 2005;108:463–77. doi: 10.1042/CS20040342.
    1. Bai TR, Cooper J, Koelmeyer T, et al. The effect of age and duration of disease on airway structure in fatal asthma. Am J Respir Crit Care Med. 2000;162:663–9. doi: 10.1164/ajrccm.162.2.9907151.
    1. Bara I, Ozier A, Tunon de Lara J-M, et al. Pathophysiology of bronchial smooth muscle remodelling in asthma. Eur Respir J. 2010;36:1174–84. doi: 10.1183/09031936.00019810.
    1. Beckett PA, Howarth PH. Pharmacotherapy and airway remodelling in asthma ? Thorax. 2003;58:163–74. doi: 10.1136/thorax.58.2.163.
    1. Benayoun L, Druilhe A, Dombret M-C, et al. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med. 2003;167:1360–8. doi: 10.1164/rccm.200209-1030OC.
    1. Berankova K, Uhlik J, Honkova L, Pohunek P. Structural changes in the bronchial mucosa of young children at risk of developing asthma. Pediatr Allergy Immunol. 2014;25:136–142. doi: 10.1111/pai.12119.
    1. Berger P, Perng DW, Thabrew H, et al. Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells. J Appl Physiol. 2001;91:1372–9.
    1. Bergeron C, Al-Ramli W, Hamid Q. Remodeling in asthma. Proc Am Thorac Soc. 2009;6:301–5. doi: 10.1513/pats.200808-089RM.
    1. Bhakta NR, Woodruff PG. Human asthma phenotypes: from the clinic, to cytokines, and back again. Immunol Rev. 2011;242:220–32. doi: 10.1111/j.1600-065X.2011.01032.x.
    1. Bisgaard H, Jensen SM, Bønnelykke K. Interaction between asthma and lung function growth in early life. Am J Respir Crit Care Med. 2012;185:1183–9. doi: 10.1164/rccm.201110-1922OC.
    1. Borthwick DW, West JD, Keighren MA, et al. Murine submucosal glands are clonally derived and show a cystic fibrosis gene-dependent distribution pattern. Am J Respir Cell Mol Biol. 1999;20:1181–9. doi: 10.1165/ajrcmb.20.6.3475.
    1. Boulet L, Sterk PJ. Airway remodelling: the future. Eur Respir J. 2007;30:831–834. doi: 10.1183/09031936.00110107.
    1. Bradding P, Walls AF, Holgate ST. The role of the mast cell in the pathophysiology of asthma. J Allergy Clin Immunol. 2006;117:1277–84. doi: 10.1016/j.jaci.2006.02.039.
    1. Bratu VA (2008) Histopathological morphometry of human endobronchial biopsies - a comparison of conventional quantitative analyses and stereological designs. Inauguraldissertation, M.D. Thesis, Philipps-University Marburg, Germany
    1. Bratu VA, Erpenbeck VJ, Fehrenbach A, et al. Cell counting in human endobronchial biopsies - Disagreement of 2D versus 3D morphometry. PLoS ONE. 2014;9(3):e92510. doi: 10.1371/journal.pone.0092510.
    1. Brightling CE, Symon FA, Holgate ST, et al. Interleukin-4 and −13 expression is co-localized to mast cells within the airway smooth muscle in asthma. Clin Exp Allergy. 2003;33:1711–6. doi: 10.1111/j.1365-2222.2003.01827.x.
    1. Brusasco V, Crimi E, Barisione G, et al. Airway responsiveness to methacholine: effects of deep inhalations and airway inflammation. J Appl Physiol. 1999;87:567–73.
    1. Burke H, Leonardi-Bee J, Hashim A, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics. 2012;129:735–44. doi: 10.1542/peds.2011-2196.
    1. Cairns JA, Walls AF. Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. J Clin Invest. 1997;99:1313–21. doi: 10.1172/JCI119290.
    1. Camateros P, Tamaoka M, Hassan M, et al. Chronic asthma-induced airway remodeling is prevented by toll-like receptor-7/8 ligand S28463. Am J Respir Crit Care Med. 2007;175:1241–9. doi: 10.1164/rccm.200701-054OC.
    1. Chen FH, Samson KT, Miura K, et al. Airway remodeling: a comparison between fatal and nonfatal asthma. J Asthma. 2004;41:631–8. doi: 10.1081/JAS-200026405.
    1. Chetta A, Zanini A, Foresi A, et al. Vascular component of airway remodeling in asthma is reduced by high dose of fluticasone. Am J Respir Crit Care Med. 2003;167:751–7. doi: 10.1164/rccm.200207-710OC.
    1. Cho JY, Miller M, Baek KJ, et al. Inhibition of airway remodeling in IL-5-deficient mice. J Clin Invest. 2004;113:551–60. doi: 10.1172/JCI19133.
    1. Cohen MD, Ciocca V, Panettieri RA. TGF-beta 1 modulates human airway smooth-muscle cell proliferation induced by mitogens. Am J Respir Cell Mol Biol. 1997;16:85–90. doi: 10.1165/ajrcmb.16.1.8998083.
    1. Cohen P, Rajah R, Rosenbloom J, Herrick DJ. IGFBP-3 mediates TGF-beta1-induced cell growth in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2000;278:L545–51.
    1. Cohn L, Homer RJ, Marinov A, et al. Induction of airway mucus production By T helper 2 (Th2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production. J Exp Med. 1997;186:1737–47. doi: 10.1084/jem.186.10.1737.
    1. Compton SJ, Cairns JA, Holgate ST, Walls AF. The role of mast cell tryptase in regulating endothelial cell proliferation, cytokine release, and adhesion molecule expression: tryptase induces expression of mRNA for IL-1 beta and IL-8 and stimulates the selective release of IL-8 from human umbilical v. J Immunol. 1998;161:1939–1946.
    1. Croisant S. Epidemiology of asthma: prevalence and burden of disease. Adv Exp Med Biol. 2014;795:17–29. doi: 10.1007/978-1-4614-8603-9_2.
    1. Crystal RG, West JB, Weibel ER, Barnes PJ (1997) The Lung. Scientific Foundations, 2nd edn. Lippincott-Raven, Philadelphia
    1. Cundall M, Sun Y, Miranda C, et al. Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids. J Allergy Clin Immunol. 2003;112:1064–71. doi: 10.1016/j.jaci.2003.08.013.
    1. Dekkers BGJ, Bos IST, Halayko AJ, et al. The laminin β1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma. Respir Res. 2010;11:170. doi: 10.1186/1465-9921-11-170.
    1. Denzler KL, Farmer SC, Crosby JR, et al. Eosinophil major basic protein-1 does not contribute to allergen-induced airway pathologies in mouse models of asthma. J Immunol. 2000;165:5509–17. doi: 10.4049/jimmunol.165.10.5509.
    1. Dezateux C, Stocks J. Lung development and early origins of childhood respiratory illness. Br Med Bull. 1997;53:40–57. doi: 10.1093/oxfordjournals.bmb.a011605.
    1. Doe C, Bafadhel M, Siddiqui S, et al. Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest. 2010;138:1140–7. doi: 10.1378/chest.09-3058.
    1. Dorscheid DR, Low E, Conforti A, et al. Corticosteroid-induced apoptosis in mouse airway epithelium: effect in normal airways and after allergen-induced airway inflammation. J Allergy Clin Immunol. 2003;111:360–6. doi: 10.1067/mai.2003.117.
    1. Doyle AD, Jacobsen EA, Ochkur SI, et al. Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice. Blood. 2013;122:781–90. doi: 10.1182/blood-2013-01-473405.
    1. Durrani SR, Viswanathan RK, Busse WW. Role of airway smooth muscle in airway remodeling. J Allergy Clin Immunol. 2011;128:439–448. doi: 10.1016/j.jaci.2011.06.002.
    1. Elias JA. Airway remodeling in asthma - unanswered questions. Am J Respir Crit Care Med. 2000;161:S168–S171. doi: 10.1164/ajrccm.161.supplement_2.a1q4-4.
    1. Evans MJ, Van Winkle LS, Fanucchi MV, et al. Fibroblast growth factor-2 in remodeling of the developing basement membrane zone in the trachea of infant rhesus monkeys sensitized and challenged with allergen. Lab Invest. 2002;82:1747–54. doi: 10.1097/01.LAB.0000043911.94235.F3.
    1. Evans MJ, Fanucchi MV, Baker GL, et al. The remodelled tracheal basement membrane zone of infant rhesus monkeys after 6 months of recovery. Clin Exp Allergy. 2004;34:1131–6. doi: 10.1111/j.1365-2222.2004.02004.x.
    1. Evans MJ, Fanucchi MV, Plopper CG, Hyde DM. Postnatal development of the lamina reticularis in primate airways. Anat Rec (Hoboken) 2010;293:947–54. doi: 10.1002/ar.20824.
    1. Fahy JV. Type 2 inflammation in asthma — present in most, absent in many. Nat Immunol. 2015;15:57–65. doi: 10.1038/nri3786.
    1. Fahy JV, Locksley RM. The airway epithelium as a regulator of th2 responses in asthma. Am J Respir Crit Care Med. 2011;184:390–2. doi: 10.1164/rccm.201107-1258ED.
    1. Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and allergic disease: The next steps toward personalized care. J Allergy Clin Immunol. 2016;135:299–310. doi: 10.1016/j.jaci.2014.12.1871.
    1. Fehrenbach H, Dittrich V, Zissler D. Eggshell fine structure of three lepidopteran pests: Cydia pomonella (L.) (Tortricidae), Heliothis virescens (Fabr.), and Spodoptera littoralis (Boisd.) (Noctuidae) Int J Insect Morphol Embryol. 1987;16:201–219. doi: 10.1016/0020-7322(87)90021-3.
    1. Ferrando RE, Nyengaard JR, Hays SR, et al. Applying stereology to measure thickness of the basement membrane zone in bronchial biopsy specimens. J Allergy Clin Immunol. 2003;112:1243–5. doi: 10.1016/j.jaci.2003.09.038.
    1. Fixman ED, Stewart A, Martin JG. Basic mechanisms of development of airway structural changes in asthma. Eur Respir J. 2007;29:379–389. doi: 10.1183/09031936.00053506.
    1. Flood-Page P, Menzies-Gow A, Phipps S, et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest. 2003;112:1029–36. doi: 10.1172/JCI17974.
    1. Foley SC, Hamid Q. Images in allergy and immunology: neutrophils in asthma. J Allergy Clin Immunol. 2007;119:1282–6. doi: 10.1016/j.jaci.2007.02.006.
    1. Foster PS, Ming Y, Matthei KI, et al. Dissociation of inflammatory and epithelial responses in a murine model of chronic asthma. Lab Invest. 2000;80:655–62. doi: 10.1038/labinvest.3780068.
    1. Foster PS, Yang M, Herbert C, Kumar RK. CD4(+) T-lymphocytes regulate airway remodeling and hyper-reactivity in a mouse model of chronic asthma. Lab Invest. 2002;82:455–62. doi: 10.1038/labinvest.3780438.
    1. Fredens K, Dahl R, Venge P. The Gordon phenomenon induced by the eosinophil cationic protein and eosinophil protein X. J Allergy Clin Immunol. 1982;70:361–6. doi: 10.1016/0091-6749(82)90025-2.
    1. Frey URS, Makkonen K, Wellman T, et al. Alterations in airway wall properties in infants with a history of wheezing disorders. Am J Respir Crit Care Med. 2000;161:1825–1829. doi: 10.1164/ajrccm.161.6.9812057.
    1. Gabehart KE, Royce SG, Maselli DJ, et al. Airway hyperresponsiveness is associated with airway remodeling but not inflammation in aging Cav1−/− mice. Respir Res. 2013;14:110. doi: 10.1186/1465-9921-14-110.
    1. GBD 2013 Mortality and Causes of Death Collaborators Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–71. doi: 10.1016/S0140-6736(14)61682-2.
    1. Gleich GJ, Adolphson CR, Leiferman KM. The biology of the eosinophilic leukocyte. Annu Rev Med. 1993;44:85–101. doi: 10.1146/annurev.me.44.020193.000505.
    1. Global Burden of Disease Study 2013 Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743–800. doi: 10.1016/S0140-6736(15)60692-4.
    1. Gomes RFM, Bates JHT. Geometric determinants of airway resistance in two isomorphic rodent species. Respir Physiol Neurobiol. 2002;130:317–25. doi: 10.1016/S0034-5687(02)00017-8.
    1. Gosens R, Grainge C. Bronchoconstriction and airway biology: Potential impact and therapeutic opportunities. Chest. 2015;147:798–803. doi: 10.1378/chest.14-1142.
    1. Grainge CL, Lau LCK, Ward JA, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med. 2011;364:2006–15. doi: 10.1056/NEJMoa1014350.
    1. Gregory LG, Mathie SA, Walker SA, et al. Overexpression of Smad2 drives house dust mite-mediated airway remodeling and airway hyperresponsiveness via activin and IL-25. Am J Respir Crit Care Med. 2010;182:143–54. doi: 10.1164/rccm.200905-0725OC.
    1. Gruber C, Kohlstedt K, Loot AE, et al. Stereological characterization of left ventricular cardiomyocytes, capillaries, and innervation in the nondiabetic, obese mouse. Cardiovasc Pathol. 2012;21:346–54. doi: 10.1016/j.carpath.2011.11.003.
    1. Harding R, Maritz G. Maternal and fetal origins of lung disease in adulthood. Semin Fetal Neonatal Med. 2012;17:67–72. doi: 10.1016/j.siny.2012.01.005.
    1. Hartley RA, Barker BL, Newby C, et al. Relationship between lung function and quantitative computed tomographic parameters of airway remodeling, air trapping, and emphysema in patients with asthma and chronic obstructive pulmonary disease: A single-center study. J Allergy Clin Immunol. 2016;137:1413–1422.e12. doi: 10.1016/j.jaci.2016.02.001.
    1. Hashimoto S, Gon Y, Takeshita I, et al. Transforming growth Factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway. Am J Respir Crit Care Med. 2001;163:152–7. doi: 10.1164/ajrccm.163.1.2005069.
    1. Henschen M, Stocks J, Brookes I, Frey U. New aspects of airway mechanics in pre-term infants. Eur Respir J. 2006;27:913–20.
    1. Herszberg B, Ramos-Barbón D, Tamaoka M, et al. Heaves, an asthma-like equine disease, involves airway smooth muscle remodeling. J Allergy Clin Immunol. 2006;118:382–8. doi: 10.1016/j.jaci.2006.03.044.
    1. Hilliard TN, Regamey N, Shute JK, et al. Airway remodelling in children with cystic fibrosis. Thorax. 2007;62:1074–80. doi: 10.1136/thx.2006.074641.
    1. Hirota N, Martin JG. Mechanisms of airway remodeling. Chest. 2013;144:1026–1032. doi: 10.1378/chest.12-3073.
    1. Hirst SJ, Barnes PJ, Twort CH. PDGF isoform-induced proliferation and receptor expression in human cultured airway smooth muscle cells. Am J Physiol. 1996;270:L415–28.
    1. Hogaboam CM, Blease K, Mehrad B, et al. Chronic airway hyperreactivity, goblet cell hyperplasia, and peribronchial fibrosis during allergic airway disease induced by Aspergillus fumigatus. Am J Pathol. 2000;156:723–32. doi: 10.1016/S0002-9440(10)64775-X.
    1. Hogg J. Peripheral lung remodelling in asthma and chronic obstructive pulmonary disease. Eur Respir J. 2004;24:893–4. doi: 10.1183/09031936.04.00110704.
    1. Holgate ST. Epithelium dysfunction in asthma. J Allergy Clin Immunol. 2007;120:1233–44–6. doi: 10.1016/j.jaci.2007.10.025.
    1. Holgate ST. The sentinel role of the airway epithelium in asthma pathogenesis. Immunol Rev. 2011;242:205–19. doi: 10.1111/j.1600-065X.2011.01030.x.
    1. Holgate ST. The sentinel role of the airway epithelium in asthma pathogenesis. Immunol Rev. 2011;242:205–19. doi: 10.1111/j.1600-065X.2011.01030.x.
    1. Holgate ST, Lackie P, Wilson S, et al. Bronchial epithelium as a key regulator of airway allergen sensitization and remodeling in asthma. Am J Respir Crit Care Med. 2000;162:S113–7. doi: 10.1164/ajrccm.162.supplement_2.ras-12.
    1. Holgate S, Davies D, Ordoñez CL, Fahy JV. Epithelial desquamation in asthma. Am J Respir Crit Care Med. 2001;164:1997. doi: 10.1164/ajrccm.164.10.correspondence_a.
    1. Holt PG, Strickland DH, Hales BJ, Sly PD. Defective respiratory tract immune surveillance in asthma: a primary causal factor in disease onset and progression. Chest. 2014;145:370–8. doi: 10.1378/chest.13-1341.
    1. Hoshino M, Nakamura Y, Sim JJ, et al. Inhaled corticosteroid reduced lamina reticularis of the basement membrane by modulation of insulin-like growth factor (IGF)-I expression in bronchial asthma. Clin Exp Allergy. 1998;28:568–77. doi: 10.1046/j.1365-2222.1998.00277.x.
    1. Hoshino M, Takahashi M, Takai Y, Sim J. Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in asthma. J Allergy Clin Immunol. 1999;104:356–63. doi: 10.1016/S0091-6749(99)70379-9.
    1. Hoshino M, Takahashi M, Takai Y, et al. Inhaled corticosteroids decrease vascularity of the bronchial mucosa in patients with asthma. Clin Exp Allergy. 2001;31:722–30. doi: 10.1046/j.1365-2222.2001.01071.x.
    1. Hsia CCW, Hyde DM, Ochs M, Weibel ER. An official research policy statement of the American Thoracic Society/European Respiratory Society: Standards for quantitative assessment of lung structure. Am J Respir Crit Care Med. 2010;181:394–418. doi: 10.1164/rccm.200809-1522ST.
    1. Hyde DM, Miller LA, Schelegle ES, et al. Asthma: a comparison of animal models using stereological methods. Eur Respir Rev. 2006;15:122–135. doi: 10.1183/09059180.00010103.
    1. Hyde DM, Tyler NK, Plopper CG. Morphometry of the respiratory tract: avoiding the sampling, size, orientation, and reference traps. Toxicol Pathol. 2007;35:41–48. doi: 10.1080/01926230601059977.
    1. Ingram JL, Kraft M. IL-13 in asthma and allergic disease: Asthma phenotypes and targeted therapies. J Allergy Clin Immunol. 2012;130:829–842. doi: 10.1016/j.jaci.2012.06.034.
    1. Ito I, Fixman ED, Asai K, et al. Platelet-derived growth factor and transforming growth factor-beta modulate the expression of matrix metalloproteinases and migratory function of human airway smooth muscle cells. Clin Exp Allergy. 2009;39:1370–80. doi: 10.1111/j.1365-2222.2009.03293.x.
    1. Jacobsen EA, Lesuer WE, Willetts L, et al. Eosinophil activities modulate the immune/inflammatory character of allergic respiratory responses in mice. Allergy. 2014;69:315–27. doi: 10.1111/all.12321.
    1. Jain VV, Businga TR, Kitagaki K, et al. Mucosal immunotherapy with CpG oligodeoxynucleotides reverses a murine model of chronic asthma induced by repeated antigen exposure. Am J Physiol Lung Cell Mol Physiol. 2003;285:L1137–46. doi: 10.1152/ajplung.00073.2003.
    1. James AL, Elliot JG, Jones RL, et al. Airway smooth muscle hypertrophy and hyperplasia in asthma. Am J Respir Crit Care Med. 2012;185:1058–1064. doi: 10.1164/rccm.201110-1849OC.
    1. Jatakanon A, Uasuf C, Maziak W, et al. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med. 1999;160:1532–9. doi: 10.1164/ajrccm.160.5.9806170.
    1. Jean D, Vrins A, Beauchamp G, Lavoie J-P. Evaluation of variations in bronchoalveolar lavage fluid in horses with recurrent airway obstruction. Am J Vet Res. 2011;72:838–42. doi: 10.2460/ajvr.72.6.838.
    1. Jeffery PK. Remodeling in Asthma and Chronic Obstructive Lung Disease. Am J Respir Crit Care Med. 2001;164:S28–S38. doi: 10.1164/ajrccm.164.supplement_2.2106061.
    1. Jeffery PK. Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2004;1:176–83. doi: 10.1513/pats.200402-009MS.
    1. Johnson JR, Wiley RE, Fattouh R, et al. Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling. Am J Respir Crit Care Med. 2004;169:378–85. doi: 10.1164/rccm.200308-1094OC.
    1. Jones RL, Noble PB, Elliot JG, James AL. Airway remodelling in COPD: It’s not asthma! Respirology. 2016;21:1347–1356. doi: 10.1111/resp.12841.
    1. Jungsuwadee P, Benkovszky M, Dekan G, et al. Repeated aerosol allergen exposure suppresses inflammation in B-cell-deficient mice with established allergic asthma. Int Arch Allergy Immunol. 2004;133:40–8. doi: 10.1159/000075252.
    1. Justice JP, Crosby J, Borchers MT, et al. CD4(+) T cell-dependent airway mucus production occurs in response to IL-5 expression in lung. Am J Physiol Lung Cell Mol Physiol. 2002;282:L1066–74. doi: 10.1152/ajplung.00195.2001.
    1. Kanbe N, Kurosawa M, Nagata H, et al. Cord blood-derived human cultured mast cells produce transforming growth factor beta1. Clin Exp Allergy. 1999;29:105–13. doi: 10.1046/j.1365-2222.1999.00459.x.
    1. Kariyawasam HH, Robinson DS. The eosinophil: the cell and its weapons, the cytokines, its locations. Semin Respir Crit Care Med. 2006;27:117–27. doi: 10.1055/s-2006-939514.
    1. Kerzel S, Wagner J, Rogosch T, et al. Composition of the immunoglobulin classic antigen-binding site regulates allergic airway inflammation in a murine model of experimental asthma. Clin Exp Allergy. 2009;39:591–601. doi: 10.1111/j.1365-2222.2008.03178.x.
    1. Kerzel S, Rogosch T, Wagner J, et al. A single D(H) gene segment is sufficient for the establishment of an asthma phenotype in a murine model of allergic airway inflammation. Int Arch Allergy Immunol. 2011;156:247–258. doi: 10.1159/000323527.
    1. Kirschvink N, Kersnak E, Leemans J, et al. Effects of age and allergen-induced airway inflammation in cats: radiographic and cytologic correlation. Vet J. 2007;174:644–51. doi: 10.1016/j.tvjl.2006.11.010.
    1. Kirschvink N, Leemans J, Delvaux F, et al. Functional, inflammatory and morphological characterisation of a cat model of allergic airway inflammation. Vet J. 2007;174:541–53. doi: 10.1016/j.tvjl.2006.11.004.
    1. Krauss-Etschmann S, Bush A, Bellusci S, et al. Of flies, mice and men: a systematic approach to understanding the early life origins of chronic lung disease. Thorax. 2012;68:380–384. doi: 10.1136/thoraxjnl-2012-201902.
    1. Kumar RK, Temelkovski J, McNeil HP, Hunter N. Airway inflammation in a murine model of chronic asthma: evidence for a local humoral immune response. Clin Exp Allergy. 2000;30:1486–92. doi: 10.1046/j.1365-2222.2000.00911.x.
    1. Kumar RK, Herbert C, Yang M, et al. Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma. Clin Exp Allergy. 2002;32:1104–11. doi: 10.1046/j.1365-2222.2002.01420.x.
    1. Kumar RK, Herbert C, Kasper M. Reversibility of airway inflammation and remodelling following cessation of antigenic challenge in a model of chronic asthma. Clin Exp Allergy. 2004;34:1796–802. doi: 10.1111/j.1365-2222.2004.02097.x.
    1. Kuperman DA, Huang X, Koth LL, et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med. 2002;8:885–9.
    1. Laitinen A, Altraja A, Kämpe M, et al. Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med. 1997;156:951–8. doi: 10.1164/ajrccm.156.3.9610084.
    1. Lambrecht BN, Hammad H. Allergens and the airway epithelium response: Gateway to allergic sensitization. J Allergy Clin Immunol. 2014;134:499–507. doi: 10.1016/j.jaci.2014.06.036.
    1. Larson SD, Schelegle ES, Walby WF, et al. Postnatal remodeling of the neural components of the epithelial-mesenchymal trophic unit in the proximal airways of infant rhesus monkeys exposed to ozone and allergen. Toxicol Appl Pharmacol. 2004;194:211–20. doi: 10.1016/j.taap.2003.09.025.
    1. Lazaar AL, Plotnick MI, Kucich U, et al. Mast cell chymase modifies cell-matrix interactions and inhibits mitogen-induced proliferation of human airway smooth muscle cells. J Immunol. 2002;169:1014–20. doi: 10.4049/jimmunol.169.2.1014.
    1. Lee JJ, McGarry MP, Farmer SC, et al. Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J Exp Med. 1997;185:2143–56. doi: 10.1084/jem.185.12.2143.
    1. Lee CG, Link H, Baluk P, et al. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med. 2004;10:1095–103. doi: 10.1038/nm1105.
    1. Lee JJ, Dimina D, Macias MP, et al. Defining a link with asthma in mice congenitally deficient in eosinophils. Science. 2004;305:1773–6. doi: 10.1126/science.1099472.
    1. Lee K-Y, Ho S-C, Lin H-C, et al. Neutrophil-derived elastase induces TGF-beta1 secretion in human airway smooth muscle via NF-kappaB pathway. Am J Respir Cell Mol Biol. 2006;35:407–14. doi: 10.1165/rcmb.2006-0012OC.
    1. Leigh R, Ellis R, Wattie J, et al. Dysfunction and remodeling of the mouse airway persist after resolution of acute allergen-induced airway inflammation. Am J Respir Cell Mol Biol. 2002;27:526–35. doi: 10.1165/rcmb.2002-0048OC.
    1. Leigh R, Ellis R, Wattie JN, et al. Type 2 cytokines in the pathogenesis of sustained airway dysfunction and airway remodeling in mice. Am J Respir Crit Care Med. 2004;169:860–7. doi: 10.1164/rccm.200305-706OC.
    1. Leung SY, Eynott P, Nath P, Chung KF. Effects of ciclesonide and fluticasone propionate on allergen-induced airway inflammation and remodeling features. J Allergy Clin Immunol. 2005;115:989–96. doi: 10.1016/j.jaci.2005.01.036.
    1. Lezmi G, Gosset P, Deschildre A, et al. Airway remodeling in preschool children with severe recurrent wheeze. Am J Respir Crit Care Med. 2015;192:164–171. doi: 10.1164/rccm.201411-1958OC.
    1. Liesker JJW, Ten Hacken NH, Zeinstra-Smith M, et al. Reticular basement membrane in asthma and COPD: similar thickness, yet different composition. Int J Chron Obstruct Pulmon Dis. 2009;4:127–35.
    1. Lødrup Carlsen KC, Carlsen K-H. Asthma in children: the road to individual asthma phenotypes. Eur Respir Monogr. 2012;56:1–9.
    1. Lötvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127:355–60. doi: 10.1016/j.jaci.2010.11.037.
    1. Lu S, Li H, Gao R, et al. IL-17A, but not IL-17F, is indispensable for airway vascular remodeling induced by exaggerated Th17 cell responses in prolonged ovalbumin-challenged mice. J Immunol. 2015;194:3557–66. doi: 10.4049/jimmunol.1400829.
    1. Lucarini L, Pini A, Gerace E, et al. Poly(ADP-ribose) polymerase inhibition with HYDAMTIQ reduces allergen-induced asthma-like reaction, bronchial hyper-reactivity and airway remodelling. J Cell Mol Med. 2014;18:468–479. doi: 10.1111/jcmm.12197.
    1. Luger EO, Fokuhl V, Wegmann M, et al. Induction of long-lived allergen-specific plasma cells by mucosal allergen challenge. J Allergy Clin Immunol. 2009;124:819–26.e4. doi: 10.1016/j.jaci.2009.06.047.
    1. Maarsingh H, Dekkers BGJ, Zuidhof AB, et al. Increased arginase activity contributes to airway remodelling in chronic allergic asthma. Eur Respir J. 2011;38:318–28. doi: 10.1183/09031936.00057710.
    1. Malavia NK, Mih JD, Raub CB, et al. IL-13 induces a bronchial epithelial phenotype that is profibrotic. Respir Res. 2008;9:27. doi: 10.1186/1465-9921-9-27.
    1. Malmström K, Pelkonen AS, Malmberg LP, et al. Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years. Thorax. 2011;66:157–62. doi: 10.1136/thx.2010.139246.
    1. Malmström K, Malmberg LP, O’Reilly R, et al. Lung function, airway remodeling, and inflammation in infants: outcome at 8 years. Ann Allergy Asthma Immunol. 2015;114:90–6. doi: 10.1016/j.anai.2014.09.019.
    1. Maritz GS, Morley CJ, Harding R. Early developmental origins of impaired lung structure and function. Early Hum Dev. 2005;81:763–71. doi: 10.1016/j.earlhumdev.2005.07.002.
    1. Martinez FD. The origins of asthma and chronic obstructive pulmonary disease in early life. Proc Am Thorac Soc. 2009;6:272–7. doi: 10.1513/pats.200808-092RM.
    1. Martinez FD, Vercelli D. Asthma. Lancet. 2013;382:1360–1372. doi: 10.1016/S0140-6736(13)61536-6.
    1. Mauroy B, Filoche M, Weibel ER, Sapoval B. An optimal bronchial tree may be dangerous. Nature. 2004;427:633–6. doi: 10.1038/nature02287.
    1. McMillan SJ, Lloyd CM. Prolonged allergen challenge in mice leads to persistent airway remodelling. Clin Exp Allergy. 2004;34:497–507. doi: 10.1111/j.1365-2222.2004.01895.x.
    1. Michalik M, Pierzchalska M, Legutko A, et al. Asthmatic bronchial fibroblasts demonstrate enhanced potential to differentiate into myofibroblasts in culture. Med Sci Monit. 2009;15:BR194–201.
    1. Miller M, Cho JY, McElwain K, et al. Corticosteroids prevent myofibroblast accumulation and airway remodeling in mice. Am J Physiol Lung Cell Mol Physiol. 2006;290:L162–9. doi: 10.1152/ajplung.00252.2005.
    1. Moir LM, Leung S-Y, Eynott PR, et al. Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats. Am J Physiol Lung Cell Mol Physiol. 2003;284:L148–59. doi: 10.1152/ajplung.00105.2002.
    1. Mühlfeld C, Ochs M. Quantitative microscopy of the lung: a problem-based approach. Part 2: stereological parameters and study designs in various diseases of the respiratory tract. Am J Physiol Lung Cell Mol Physiol. 2013;305:L205–21. doi: 10.1152/ajplung.00427.2012.
    1. Nakashima AS, Prado CM, Lanças T, et al. Oral tolerance attenuates changes in in vitro lung tissue mechanics and extracellular matrix remodeling induced by chronic allergic inflammation in guinea pigs. J Appl Physiol. 2008;104:1778–85. doi: 10.1152/japplphysiol.00830.2007.
    1. Okumura S, Sagara H, Fukuda T, et al. FcepsilonRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells. J Allergy Clin Immunol. 2005;115:272–9. doi: 10.1016/j.jaci.2004.10.004.
    1. Olivieri D, Chetta A, Del Donno M, et al. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo-controlled study. Am J Respir Crit Care Med. 1997;155:1864–71. doi: 10.1164/ajrccm.155.6.9196087.
    1. Olivo CR, Vieira RP, Arantes-Costa FM, et al. Effects of aerobic exercise on chronic allergic airway inflammation and remodeling in guinea pigs. Respir Physiol Neurobiol. 2012;182:81–7. doi: 10.1016/j.resp.2012.05.004.
    1. Ordoñez C, Ferrando R, Hyde DM, et al. Epithelial desquamation in asthma: artifact or pathology? Am J Respir Crit Care Med. 2000;162:2324–9. doi: 10.1164/ajrccm.162.6.2001041.
    1. Padrid P. Feline asthma. Diagnosis and treatment. Vet Clin North Am Small Anim Pract. 2000;30:1279–93. doi: 10.1016/S0195-5616(00)06007-1.
    1. Pantano C, Ather JL, Alcorn JF, et al. Nuclear factor-kappaB activation in airway epithelium induces inflammation and hyperresponsiveness. Am J Respir Crit Care Med. 2008;177:959–69. doi: 10.1164/rccm.200707-1096OC.
    1. Pascual RM, Peters SP. Airway remodeling contributes to the progressive loss of lung function in asthma: An overview. J Allergy Clin Immunol. 2005;116:477–486. doi: 10.1016/j.jaci.2005.07.011.
    1. Pelkonen AS, Malmberg LP, Lindahl H, et al. Airway Remodeling and Inflammation in Symptomatic Infants with Reversible Airflow Obstruction. Crit Care Med. 2005;171:722–7. doi: 10.1164/rccm.200410-1404OC.
    1. Pepe C, Foley S, Shannon J, et al. Differences in airway remodeling between subjects with severe and moderate asthma. J Allergy Clin Immunol. 2005;116:544–9. doi: 10.1016/j.jaci.2005.06.011.
    1. Perret JL, Walters H, Johns D, et al. Mother’s smoking and complex lung function of offspring in middle age: A cohort study from childhood. Respirology. 2016;11:911–919. doi: 10.1111/resp.12750.
    1. Pigati PA, Righetti RF, Possa SS, et al. Y-27632 is associated with corticosteroid-potentiated control of pulmonary remodeling and inflammation in guinea pigs with chronic allergic inflammation. BMC Pulm Med. 2015;15:85. doi: 10.1186/s12890-015-0073-4.
    1. Pini L, Torregiani C, Martin JG, et al. Airway remodeling in allergen-challenged Brown Norway rats: distribution of proteoglycans. Am J Physiol Lung Cell Mol Physiol. 2006;290:L1052–8. doi: 10.1152/ajplung.00122.2005.
    1. Plopper CG, Smiley-Jewell SM, Miller LA, et al. Asthma/allergic airways disease: does postnatal exposure to environmental toxicants promote airway pathobiology? Toxicol Pathol. 2007;35:97–110. doi: 10.1080/01926230601132030.
    1. Pohunek P, Warner JO, Torzíková J, et al. Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma. Pediatr Allergy Immunol. 2005;16:43–51. doi: 10.1111/j.1399-3038.2005.00239.x.
    1. Possa SS, Charafeddine HT, Righetti RF, et al. Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation. Am J Physiol Lung Cell Mol Physiol. 2012;303:L939–52. doi: 10.1152/ajplung.00034.2012.
    1. Prado CM, Leick-Maldonado EA, Kasahara DI, et al. Effects of acute and chronic nitric oxide inhibition in an experimental model of chronic pulmonary allergic inflammation in guinea pigs. Am J Physiol Lung Cell Mol Physiol. 2005;289:L677–83. doi: 10.1152/ajplung.00010.2005.
    1. Prins JR, Hylkema MN, Erwich JJHM, et al. Smoking during pregnancy influences the maternal immune response in mice and humans. Am J Obstet Gynecol. 2012;207:76.e1–76.e14. doi: 10.1016/j.ajog.2012.04.017.
    1. Ramos-Barbón D, Presley JF, Hamid QA, et al. Antigen-specific CD4+ T cells drive airway smooth muscle remodeling in experimental asthma. J Clin Invest. 2005;115:1580–9. doi: 10.1172/JCI19711.
    1. Rankin JA, Picarella DE, Geba GP, et al. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc Natl Acad Sci U S A. 1996;93:7821–5. doi: 10.1073/pnas.93.15.7821.
    1. Reddel HK, Bateman ED, Becker A, et al. A summary of the new GINA strategy : a roadmap to asthma control. Eur Respir J. 2015;46:622–639. doi: 10.1183/13993003.00853-2015.
    1. Regamey N, Ochs M, Hilliard TN, et al. Increased airway smooth muscle mass in children with asthma, cystic fibrosis, and non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2008;177:837–843. doi: 10.1164/rccm.200707-977OC.
    1. Richter A, Puddicombe SM, Lordan JL, et al. The contribution of interleukin (IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. Am J Respir Cell Mol Biol. 2001;25:385–91. doi: 10.1165/ajrcmb.25.3.4437.
    1. Robinson DS, Damia R, Zeibecoglou K, et al. CD34(+)/interleukin-5Ralpha messenger RNA+ cells in the bronchial mucosa in asthma: potential airway eosinophil progenitors. Am J Respir Cell Mol Biol. 1999;20:9–13. doi: 10.1165/ajrcmb.20.1.3449.
    1. Robinson NE, Olszewski MA, Boehler D, et al. Relationship between clinical signs and lung function in horses with recurrent airway obstruction (heaves) during a bronchodilator trial. Equine Vet J. 2000;32:393–400. doi: 10.2746/042516400777591147.
    1. Roeder T, Isermann K, Kabesch M. Drosophila in asthma research. Am J Respir Crit Care Med. 2009;179:979–83. doi: 10.1164/rccm.200811-1777PP.
    1. Rühle H. Das larvale Tracheensystem von Drosophila melanogaster Meigen und seine Variabilität. Z Wiss Zool. 1932;141:159–245.
    1. Saetta M, Turato G. Airway pathology in asthma. Eur Respir J. 2001;18:18–23. doi: 10.1183/09031936.01.00229501.
    1. Saglani S, Lloyd CM. Novel concepts in airway inflammation and remodelling in asthma. Eur Respir J. 2015;46:1796–1804. doi: 10.1183/13993003.01196-2014.
    1. Saglani S, Payne DN, Zhu J, et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med. 2007;176:858–64. doi: 10.1164/rccm.200702-212OC.
    1. Sapienza S, Du T, Eidelman DH, et al. Structural changes in the airways of sensitized brown Norway rats after antigen challenge. Am Rev Respir Dis. 1991;144:423–7. doi: 10.1164/ajrccm/144.2.423.
    1. Sehmi R, Dorman S, Baatjes A, et al. Allergen-induced fluctuation in CC chemokine receptor 3 expression on bone marrow CD34+ cells from asthmatic subjects: significance for mobilization of haemopoietic progenitor cells in allergic inflammation. Immunology. 2003;109:536–46. doi: 10.1046/j.1365-2567.2003.01686.x.
    1. Sel S, Wegmann M, Dicke T, et al. Effective prevention and therapy of experimental allergic asthma using a GATA-3-specific DNAzyme. J Allergy Clin Immunol. 2008;121:910–916.e5. doi: 10.1016/j.jaci.2007.12.1175.
    1. Setlakwe EL, Lemos KR, Lavoie-Lamoureux A, et al. Airway collagen and elastic fiber content correlates with lung function in equine heaves. Am J Physiol Lung Cell Mol Physiol. 2014;307:L252–60. doi: 10.1152/ajplung.00019.2014.
    1. Shaw DE, Berry MA, Hargadon B, et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest. 2007;132:1871–5. doi: 10.1378/chest.07-1047.
    1. Shinagawa K, Kojima M. Mouse model of airway remodeling: strain differences. Am J Respir Crit Care Med. 2003;168:959–67. doi: 10.1164/rccm.200210-1188OC.
    1. Siddiqui S, Novali M, Tsuchiya K, et al. The modulation of large airway smooth muscle phenotype and effects of epidermal growth factor receptor inhibition in the repeatedly allergen-challenged rat. Am J Physiol Lung Cell Mol Physiol. 2013;304:L853–62. doi: 10.1152/ajplung.00047.2012.
    1. Snibson KJ, Bischof RJ, Slocombe RF, Meeusen EN. Airway remodelling and inflammation in sheep lungs after chronic airway challenge with house dust mite. Clin Exp Allergy. 2005;35:146–52. doi: 10.1111/j.1365-2222.2005.02137.x.
    1. Sonnenschein-van der Voort AMM, Arends LR, de Jongste JC, et al. Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children. J Allergy Clin Immunol. 2014;133:1317–29. doi: 10.1016/j.jaci.2013.12.1082.
    1. Sonnenschein-van der Voort AMM, Howe LD, Granell R, et al. Influence of childhood growth on asthma and lung function in adolescence. J Allergy Clin Immunol. 2015;135:1435–43. doi: 10.1016/j.jaci.2014.10.046.
    1. Sont JK, Willems LN, Bel EH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med. 1999;159:1043–51. doi: 10.1164/ajrccm.159.4.9806052.
    1. Specht S, Saeftel M, Arndt M, et al. Lack of eosinophil peroxidase or major basic protein impairs defense against murine filarial infection. Infect Immun. 2006;74:5236–43. doi: 10.1128/IAI.00329-06.
    1. Spycher BD, Silverman M, Kuehni CE. Phenotypes of childhood asthma: Are they real? Clin Exp Allergy. 2010;40:1130–1141. doi: 10.1111/j.1365-2222.2010.03541.x.
    1. Steenwinckel V, Louahed J, Orabona C, et al. IL-13 mediates in vivo IL-9 activities on lung epithelial cells but not on hematopoietic cells. J Immunol. 2007;178:3244–51. doi: 10.4049/jimmunol.178.5.3244.
    1. Sterio DC. The unbiased estimation of number and sizes of arbitrary particles using the disector. J Microsc. 1984;134:127–36. doi: 10.1111/j.1365-2818.1984.tb02501.x.
    1. Stocks J, Hislop A, Sonnappa S. Early lung development: Lifelong effect on respiratory health and disease. Lancet Respir Med. 2013;1:728–742. doi: 10.1016/S2213-2600(13)70118-8.
    1. Svanes C, Koplin J, Skulstad SM, et al. (2016) Father’s environment before conception and asthma risk in his children: A multi-generation analysis of the Respiratory Health In Northern Europe study. doi: 10.1093/ije/dyw151
    1. Takeda N, Maghni K, Daigle S, et al. Long-term pathologic consequences of acute irritant-induced asthma. J Allergy Clin Immunol. 2009;124:975–81.e1. doi: 10.1016/j.jaci.2009.08.008.
    1. Tam A, Wadsworth S, Dorscheid D, et al. The airway epithelium: more than just a structural barrier. Ther Adv Respir Dis. 2011;5:255–73. doi: 10.1177/1753465810396539.
    1. Tang W, Geba GP, Zheng T, et al. Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodeling, and airways obstruction. J Clin Invest. 1996;98:2845–53. doi: 10.1172/JCI119113.
    1. Tchougounova E, Forsberg E, Angelborg G, et al. Altered processing of fibronectin in mice lacking heparin. a role for heparin-dependent mast cell chymase in fibronectin degradation. J Biol Chem. 2001;276:3772–7. doi: 10.1074/jbc.M008434200.
    1. Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med. 1998;188:1307–20. doi: 10.1084/jem.188.7.1307.
    1. Temann U-A, Ray P, Flavell RA. Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology. J Clin Invest. 2002;109:29–39. doi: 10.1172/JCI0213696.
    1. Temelkovski J, Hogan SP, Shepherd DP, et al. An improved murine model of asthma: selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen. Thorax. 1998;53:849–56. doi: 10.1136/thx.53.10.849.
    1. Tigani B, Cannet C, Karmouty-Quintana H, et al. Lung inflammation and vascular remodeling after repeated allergen challenge detected noninvasively by MRI. Am J Physiol Lung Cell Mol Physiol. 2007;292:L644–53. doi: 10.1152/ajplung.00122.2006.
    1. Tran M-UT, Weir AJ, Fanucchi MV, et al. Smooth muscle hypertrophy in distal airways of sensitized infant rhesus monkeys exposed to house dust mite allergen. Clin Exp Allergy. 2004;34:1627–33. doi: 10.1111/j.1365-2222.2004.02057.x.
    1. Trifilieff A, El-Hashim A, Bertrand C. Time course of inflammatory and remodeling events in a murine model of asthma: effect of steroid treatment. Am J Physiol Lung Cell Mol Physiol. 2000;279:L1120–8.
    1. Trigg CJ, Manolitsas ND, Wang J, et al. Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma. Am J Respir Crit Care Med. 1994;150:17–22. doi: 10.1164/ajrccm.150.1.8025745.
    1. Tzou P, Ohresser S, Ferrandon D, et al. Tissue-specific inducible expression of antimicrobial peptide genes in Drosophila surface epithelia. Immunity. 2000;13:737–48. doi: 10.1016/S1074-7613(00)00072-8.
    1. Undem BJ, McAlexander M, Hunter DD. Neurobiology of the upper and lower airways. Allergy. 1999;54:81–93. doi: 10.1111/j.1398-9995.1999.tb04409.x.
    1. Usemann J, Fuchs O, Anagnostopoulou P, et al. Predictive value of exhaled nitric oxide in healthy infants for asthma at school age. Eur Respir J. 2016;48:912–930. doi: 10.1183/13993003.00439-2016.
    1. Van Der Velden J, Sum G, Barker D, et al. K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma. PLoS ONE. 2013;8:e66886. doi: 10.1371/journal.pone.0066886.
    1. Venkatesan N, Siddiqui S, Jo T, et al. Allergen-induced airway remodeling in brown norway rats: structural and metabolic changes in glycosaminoglycans. Am J Respir Cell Mol Biol. 2012;46:96–105. doi: 10.1165/rcmb.2011-0014OC.
    1. Verloop MC. On the arteriae bronchiales and their anastomosing with the arteria pulmonalis in some rodents; a micro-anatomical study. Acta Anat (Basel) 1949;7:1–32. doi: 10.1159/000140373.
    1. Wagner C, Isermann K, Fehrenbach H, Roeder T. Molecular architecture of the fruit fly’s airway epithelial immune system. BMC Genomics. 2008;9:446. doi: 10.1186/1471-2164-9-446.
    1. Walter DM, McIntire JJ, Berry G, et al. Critical role for IL-13 in the development of allergen-induced airway hyperreactivity. J Immunol. 2001;167:4668–75. doi: 10.4049/jimmunol.167.8.4668.
    1. Wang S-W, Oh CK, Cho SH, et al. Amphiregulin expression in human mast cells and its effect on the primary human lung fibroblasts. J Allergy Clin Immunol. 2005;115:287–94. doi: 10.1016/j.jaci.2004.11.037.
    1. Ward C, Pais M, Bish R, et al. Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax. 2002;57:309–16. doi: 10.1136/thorax.57.4.309.
    1. Wegmann M, Fehrenbach H, Fehrenbach A, et al. Involvement of distal airways in a chronic model of experimental asthma. Clin Exp Allergy. 2005;35:1263–71. doi: 10.1111/j.1365-2222.2005.02306.x.
    1. Wegmann M, Göggel R, Sel S, et al. Effects of a low-molecular-weight CCR-3 antagonist on chronic experimental asthma. Am J Respir Cell Mol Biol. 2007;36:61–7. doi: 10.1165/rcmb.2006-0188OC.
    1. Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet. 2006;368:804–813. doi: 10.1016/S0140-6736(06)69290-8.
    1. Wenzel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin Exp Allergy. 2012;42:650–8. doi: 10.1111/j.1365-2222.2011.03929.x.
    1. Wenzel SE, Balzar S, Cundall M, Chu HW. Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair. J Allergy Clin Immunol. 2003;111:1345–52. doi: 10.1067/mai.2003.1464.
    1. Whittaker L, Niu N, Temann U-A, et al. Interleukin-13 mediates a fundamental pathway for airway epithelial mucus induced by CD4 T cells and interleukin-9. Am J Respir Cell Mol Biol. 2002;27:593–602. doi: 10.1165/rcmb.4838.
    1. Woodruff PG, Innes AL. Quantitative morphology using bronchial biopsies. Eur Respir Rev. 2006;15:157–161. doi: 10.1183/09059180.00010106.
    1. Woodruff PG, Dolganov GM, Ferrando RE, et al. Hyperplasia of smooth muscle in mild to moderate asthma without changes in cell size or gene expression. Am J Respir Crit Care Med. 2004;169:1001–6. doi: 10.1164/rccm.200311-1529OC.
    1. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117:524–9. doi: 10.1172/JCI31487.
    1. Xie S, Sukkar MB, Issa R, et al. Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-beta. Am J Physiol Lung Cell Mol Physiol. 2007;293:L245–53. doi: 10.1152/ajplung.00068.2007.
    1. Zhao Y, Yang J, Gao Y-D, Guo W. Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol. 2010;151:297–307. doi: 10.1159/000250438.
    1. Zhao J, Lloyd CM, Noble A. Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling. Mucosal Immunol. 2013;6:335–46. doi: 10.1038/mi.2012.76.
    1. Zhu Z, Homer RJ, Wang Z, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999;103:779–88. doi: 10.1172/JCI5909.
    1. Zissler UM, Bieren JE, Jakwerth CA, et al. Current and future biomarkers in allergic asthma. Allergy. 2016;71:475–94. doi: 10.1111/all.12828.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever