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Review

New perspectives in bronchial asthma: pathological, immunological alterations, biological targets, and pharmacotherapy

&
Pages 521-544 | Received 01 Jun 2020, Accepted 05 Sep 2020, Published online: 27 Sep 2020

References

  • Croisant S. Epidemiology of asthma: prevalence and burden of disease. Adv Exp Med Biol. 2014;795:17–29.
  • Global initiative for asthma global strategy for asthma management and prevention. 2017.
  • Barnes PJ. Asthma-COPD overlap. Chest. 2016;149(1):7–8.
  • Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716–725.
  • Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2008;8(3):183–192.
  • Custovic A, Johnston SL, Pavord I, et al. EAACI position statement on asthma exacerbations and severe asthma. Allergy. 2013;68(12):1520–1531.
  • Holgate ST, Polosa R. Treatment strategies for allergy and asthma. Nat Rev Immunol. 2008;8(3):218–230.
  • Martinez FD, Vercelli D. Asthma. The Lancet. 2013;382(9901):1360–1372.
  • Casale TB. Biologics and biomarkers for asthma, urticaria, and nasal polyposis. J Allergy Clin Immunol. 2017;139(5):1411–1421.
  • Berry A, Busse WW. Biomarkers in asthmatic patients: has their time come to direct treatment? J Allergy Clin Immunol. 2016;137(5):1317–1324.
  • Stokes JR, Casale TB. Characterization of asthma endotypes: implications for therapy. Ann Allergy Asthma Immunol. 2016;117(2):121–125.
  • Holgate ST, Davies DE, Powell RM, et al. Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms. Eur Respir J. 2007;29(4):793–803.
  • Platts-Mills TA, Erwin EA, Heymann PW, et al. Pro: the evidence for a causal role of dust mites in asthma. Am J Respir Crit Care Med. 2009;180(2):109–113.
  • Thomson NC. The role of environmental tobacco smoke in the origins and progression of asthma. Curr Allergy Asthma Rep. 2007;7(4):303–309.
  • Ford ES. The epidemiology of obesity and asthma. J Allergy Clin Immunol. 2005;115(5):897–909.
  • Wood LG, Gibson PG. Adiponectin: the link between obesity and asthma in women? Am J Respir Crit Care Med. 2012;186(1):1–10.
  • Bel EH. Another piece to the puzzle of the “obese female asthma” phenotype. Am J Respir Crit Care Med. 2013;188(3):263–270.
  • Ramsay C, Celedon J. The hygiene hypothesis and asthma. Curr Opin Pulm Med. 2005;11:14–20.
  • Moore WC, Pascual RM. Update in asthma 2009. Am J Respir Crit Care Med. 2010;181(11):1181–1187.
  • Holgate ST. The acetaminophen enigma in asthma. Am J Respir Crit Care Med. 2011;183(2):147–151.
  • Eneli I, Sadri K, Camargo C, et al. Acetaminophen and the risk of asthma: the epidemiologic and pathophysiologic evidence. Chest. 2005;127(2):604–612.
  • Farooque SP, Lee TH. Aspirin-sensitive respiratory disease. Annu Rev Physiol. 2009; 71:465–487.
  • Kim CH, Ahn JH, Kim SJ, et al. Co-administration of vaccination with DNA encoding T cell epitope on the Der p and BCG inhibited airway remodeling in a murine model of chronic asthma. J Asthma. 200;43(5):345–353.
  • 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(3):378–385.
  • Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010;11(7):577–584.
  • Kim J, Merry AC, Nemzek JA, et al. Eotaxin represents the principal eosinophil chemoattractant in a novel murine asthma model induced by house dust containing cockroach allergens. J Immunol. 2001;167(5):2808–2815.
  • Sarpong SB, Zhang LY, Kleeberger SR. A novel mouse model of experimental asthma. Int Arch Allergy Immunol. 2003;132(4):346–354.
  • Cates EC, Fattouh R, Wattie J, et al. Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF-mediated mechanism. J Immunol. 2004;173(10):6384–6392.
  • Havaux X, Zeine A, Dits A, et al. A new mouse model of lung allergy induced by the spores of Alternaria alternata and Cladosporium herbarum molds. Clin Exp Immunol. 2005;139(2):179–188.
  • Boulet LP, Turcotte H, Laprise C, et al. Comparative degree and type of sensitization to common ovalbumin (OVA) indoor and outdoor allergens in subjects with allergic rhinitis and/or asthma. Clin Exp Allergy. 1997;27(1):52–59.
  • Barrett NA, Maekawa A, Rahman OM, et al. Dectin-2 recognition of house dust mite triggers cysteinyl leukotriene generation by dendritic cells. J Immunol. 2009;182(2):1119–1128.
  • Plantinga M, Guilliams M, Vanheerswynghels M, et al. Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity. 2013;38(2):322–335.
  • Gregory LG, Lloyd CM. Orchestrating house dust mite-associated allergy in the lung. Trends Immunol. 2011;32(9):402–411.
  • Kumar RK, Herbert C, Foster PS. The “classical” ovalbumin challenge model of asthma in mice. Curr Drug Targets. 2008;9(6):485–494.
  • Farraj AK, Harkema JR, Jan TR, et al. Immune responses in the lung and local lymph node of A/J mice to intranasal sensitization and challenge with adjuvant-free ovalbumin. Toxicol Pathol. 2003;15:151–165.
  • Barrett EG, Rudolph K, Bowen LE, et al. Effect of inhaled ultrafine carbon particles on the allergic airway response in ragweed-sensitized dogs. Inhal Toxicol. 2003;31:432–447.
  • Arruda LK, Vailes LD, Mann BJ, et al. Molecular cloning of a major cockroach (Blattella germanica) allergen, Bla g 2 Sequence homology to the aspartic proteases. J Biol Chem. 1995;270(33):19563–19568.
  • O'Donnell IJ, Mitchell GF. An investigation of the allergens of Ascaris lumbricoides using a radioallergosorbent test (RAST) and sera of naturally infected humans: comparison with an allergen for mice identified by a passive cutaneous anaphylaxis test. Aust J Biol Sci. 1978;31(5):459–487.
  • 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(3):541–553.
  • Takazono T, Sheppard DC. Aspergillus in chronic lung disease: modeling what goes on in the airways. Med Mycol. 2017;55(1):39–47.
  • Taramarcaz P, Lambelet B, Clot B, et al. Ragweed (Ambrosia) progression and its health risks: will Switzerland resist this invasion? Swiss Med Wkly. 2005;135(37-38):538–548.
  • Out TA, Wang SZ, Rudolph K, et al. Local T-cell activation after segmental allergen challenge in the lungs of allergic dogs. Immunology. 2002;105(4):499–508.
  • Vandenplas O, Raulf M. Occupational latex allergy: the current state of affairs. Curr AllergyAsthma Rep. 2017;17:14.
  • Brewster CE, Howarth PH, Djukanovic R, et al. Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol. 1990;3(5):507–511.
  • Hamid Q, Tulic M. Immunobiology of asthma. Annu Rev Physiol. 2009;71:489–507.
  • Rose MC, Gendler SJ. Airway mucin genes and gene products. In: Rogers DF, Lethem DI, editors Airway mucus: basic mechanisms and clinical perspectives. Boston: Birkhauser Verlag; 1997.
  • Barnes PJ. Principles of asthma-asthma mechanisms. Medicine. 2016;44(5):265–270.
  • Holgate ST, Wenzel S, Postma DS, et al. Asthma. Nat Rev Dis Primers. 2015;1:15025.
  • Valero A, Quirce S, Davila I, et al. Allergic respiratory disease: different allergens, different symptoms. Allergy. 2017;72(9):1306–1316.
  • Bousquet J, Arnavielhe S, Bedbrook A, MASK study group, et al. The Allergic Rhinitis and its Impact on Asthma (ARIA) score of allergic rhinitis using mobile technology correlates with quality of life: the MASK study. Allergy. 2018;73(2):505–510.
  • Del Giacco SR, Bakirtas A, Bel E, et al. Allergy in severe asthma. Allergy. 2017;72(2):207–220.
  • Deo SS, Mistry KJ, Kakade AM, et al. Role played by Th2 type cytokines in IgE mediated allergy and asthma. Lung India. 2010;27(2):66–71.
  • Hassani M, Koenderman L. Immunological and hematological effects of IL-5(Rα)-targeted therapy: an overview. Allergy. 2018;73(10):1979–1988.
  • Mitamura Y, Nunomura S, Nanri Y, et al. The IL-13/periostin/IL-24 pathway causes epidermal barrier dysfunction in allergic skin inflammation. Allergy. 2018;73(9):1881–1891.
  • Lei Z, Liu G, Huang Q, et al. SCF and IL-31 rather than IL-17 and BAFF are potential indicators in patients with allergic asthma. Allergy. 2007;63(3):327–332.
  • Dong Q, Louahed J, Vink A, et al. IL-9 induces chemokine expression in lung epithelial cells and baseline airway eosinophilia in transgenic mice. Eur J Immunol. 1999;29(7):2130–2139.
  • Eberl G, Colonna M, Di Santo JP, et al. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science. 2015;348(6237):aaa6566.
  • Rigas D, Lewis G, Aron JL, et al. Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction. J Allergy Clin Immunol. 2017;139(5):1468–1477.
  • Ohtomo T, Kaminuma O, Yamada J, et al. Eosinophils are required for the induction of bronchial hyperresponsiveness in a Th transfer model of BALB/c background. Int Arch Allergy Immunol. 2010;152(1):79–82.
  • Xiao X, Fan Y, Li J, et al. Guidance of super-enhancers in regulation of IL-9 induction and airway inflammation. J Exp Med. 2018;215(2):559–574.
  • Chen H, Zhang L, Wang P, et al. mTORC2 controls Th9 polarization and allergic airway inflammation. Allergy. 2017;72(10):1510–1520.
  • Jia L, Wang Y, Li J, et al. Detection of IL-9 producing T cells in the PBMCs of allergic asthmatic patients. BMC Immunol. 2017;18(1):38.
  • Gill MA. The role of dendritic cells in asthma. J Allergy Clin Immunol. 2012;129(4):889–901.
  • Vroman H, Hendriks RW, Kool M. Dendritic cell subsets in asthma: impaired tolerance or exaggerated inflammation? Front Immunol. 2017;8:941.
  • Khare A, Krishnamoorthy N, Oriss TB, et al. Cutting edge: inhaled antigen upregulates retinaldehyde dehydrogenase in lung CD103+ but not plasmacytoid dendritic cells to induce Foxp3 de novo in CD4+ T cells and promote airway tolerance. J Immunol. 2013;191(1):25–29.
  • Norimoto A, Hirose K, Iwata A, et al. Dectin-2 promotes house dust mite-induced T helper type 2 and type 17 cell differentiation and allergic airway inflammation in mice. Am J Respir Cell Mol Biol. 2014;51:201–209.
  • Iwamura C, Nakayama T. Role of CD1d- and MR1-restricted T cells in asthma. Front Immunol. 2018;9:1942
  • Carpio-Pedroza JC, Vaughan G, del Rio-Navarro BE, et al. Participation of CD161(+) and invariant natural killer T cells in pediatric asthma exacerbations. Allergy Asthma Proc. 2013;34(1):84–92.
  • Nakagome K, Nagata M. Involvement and possible role of eosinophils in asthma exacerbation. Front Immunol. 2018;9:2220.
  • Terl M, Sedlak V, Cap P, et al. Asthma management: a new phenotype-based approach using presence of eosinophilia and allergy. Allergy. 2017;72(9):1279–1287.
  • Wong DT, Elovic A, Matossian K, et al. Eosinophils from patients with blood eosinophilia express transforming growth factor beta 1. Blood. 1991;78(10):2702–2707.
  • Laitinen LA, Laitinen A, Haahtela T, et al. Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet. 1993;341(8851):989–990.
  • Amin K. The role of mast cells in allergic inflammation. Respir Med. 2012;106(1):9–14.
  • Ro M, Lee AJ, Kim JH. 5-/12-Lipoxygenase-linked cascade contributes to the IL-33-induced synthesis of IL-13 in mast cells, thus promoting asthma development. Allergy. 2018;73(2):350–360.
  • Fajt ML, Gelhaus SL, Freeman B, et al. Prostaglandin D(2) pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J Allergy Clin Immunol. 2013;131(6):1504–1512.
  • Matucci A, Vultaggio A, Maggi E, et al. Is IgE or eosinophils the key player in allergic asthma pathogenesis? Are we asking the right question?. Respir Res. 2018;19(1):113
  • Schroeder JT, Bieneman AP, Chichester KL, et al. Decreases in human dendritic cell-dependent T(H)2-like responses after acute in vivo IgE neutralization. J Allergy Clin Immunol. 2010;125(4):896–901.
  • Khan SH, Grayson MH. Cross-linking IgE augments human conventional dendritic cell production of CC chemokine ligand 28. J Allergy Clin Immunol. 2010;125(1):265–267.
  • Wittekindt OH. Tight junctions in pulmonary epithelia during lung inflammation. Pflugers Arch. 2017;469(1):135–147.
  • Chemuturi NV, Hayden P, Klausner M, et al. Comparison of human tracheal/bronchial epithelial cell culture and bovine nasal respiratory explants for nasal drug transport studies. J Pharm Sci. 2005;94(9):1976–1985.
  • Licona-Limon P, Kim LK, Palm NW, et al. TH2, allergy and group 2 innate lymphoid cells. Nat Immunol. 2013;14(6):536–542.
  • Roan F, Obata-Ninomiya K, Ziegler SF. Epithelial cell-derived cytokines: more than just signaling the alarm. J Clin Invest. 2019;129(4):1441–1451.
  • Sugita K, Steer CA, Martinez-Gonzalez I, et al. Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients. J Allergy Clin Immunol. 2018;141(1):300–310 e11.
  • James A, Janson C, Malinovschi A, et al. Serum periostin relates to type-2 inflammation and lung function in asthma: data from the large population-based cohort Swedish GA(2)LEN. Allergy. 2017;72(11):1753–1760.
  • Izuhara K, Conway SJ, Moore BB, et al. Roles of periostin in respiratory disorders. Am J Respir Crit Care Med. 2016;193(9):949–956.
  • Barnes PJ, Chung KF, Page CP. Inflammatory mediators of asthma: an update. Pharmacol Rev. 1998;50(4):515–596.
  • Spina D. Asthma mediators: current views. J Pharm Pharmacol. 2000;52(2):125–145.
  • Ogawa Y, Calhoun WJ. The role of leukotrienes in airway inflammation. J Allergy Clin Immunol. 2006;118(4):789–798.
  • Roquet A, Dahlen B, Kumlin M, et al. Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med. 1997;155(6):1856–1863.
  • Karasawa K. Clinical aspects of plasma platelet-activating factor acetylhydrolase. Biochim Biophys Acta. 2006;1761(11):1359–1372.
  • Ito S, Noguchi E, Shibasaki M, et al. Evidence for an association between plasma platelet-activating factor acetylhydrolase deficiency and increased risk of childhood atopic asthma. J Hum Genet. 2002;47(2):99–101.
  • O’Byrne PM. Cytokines or their antagonists for the treatment of asthma. Chest. 2006;130(1):244–250.
  • Halwani R, Al-Muhsen S, Hamid Q. T helper 17 cells in airway diseases: from laboratory bench to bedside. Chest. 2013;143(2):494–501.
  • Humbles AA, Lu B, Nilsson CA, et al. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature. 2000;406(6799):998–1001.
  • Kohl J, Wills-Karp M. A dual role for complement in allergic asthma. Curr Opin Pharmacol. 2007;7(3):283–289.
  • Cross CE, van der Vliet A, Eiserich JP. Peroxidases wheezing their way into asthma. Am J Respir Crit Care Med. 2001;164(7):1102–1103.
  • Hew M, Bhavsar P, Torrego A, et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J Respir Crit Care Med. 2006;174(2):134–141.
  • Comhair SAA, Ricci KS, Arroliga M, et al. Correlation of systemic superoxide dismutase deficiency to airflow obstruction in asthma. Am J Respir Crit Care Med. 2005;172(3):306–313.
  • Dosanjh A, Zuraw B. Endothelin-1 (ET-1) decreases human bronchial epithelial cell migration and proliferation: Implications for airway remodeling in asthma. J Asthma. 2003;40(8):883–886.
  • Gawlik R, Jastrzebski D, Ziora D, et al. Concentration of endothelin in plasma and BAL fluid from asthmatic patients. J Physiol Pharmacol. 2006;57:103–110.
  • Shi-Wen X, Chen Y, Denton CP, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell. 2004;15(6):2707–2719.
  • De Sanctis G, Maclean JA, Hamada K, et al. Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma. J Exp Med. 1999;189(10):1621–1630.
  • Kharitonov SA, Gonio F, Kelly C, et al. Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children. Eur Respir J. 2003;21(3):433–438.
  • Gaston B, Kelly R, Urban P, et al. Buffering airway acid decreases exhaled nitric oxide in asthma. J Allergy Clin Immunol. 2006;118(4):817–822.
  • Robbins RA, Hadeli K, Nelson D, et al. Nitric oxide, peroxynitrite, and lower respiratory tract inflammation. Immunopharmacol. 2000;48(3):217–221.
  • Pettipher R, Hansel TT, Armer R. Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov. 2007;6(4):313–325.
  • Gonem S, Berair R, Singapuri A, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2016;4(9):699–707.
  • Montuschi P, Kharitonov SA, Ciabattoni G, et al. Exhaled leukotrienes and prostaglandins in COPD. Thorax. 2003;58(7):585–588.
  • Jo EK, Kim JK, Shin DM, et al. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2016;13(2):148–159.
  • Kim RY, Pinkerton JW, Gibson PG, et al. Inflammasomes in COPD and neutrophilic asthma. Thorax. 2015;70(12):1199–1201.
  • Bruchard M, Rebe C, Derangere V, et al. The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nat Immunol. 2015;16(8):859–870.
  • Franklin BS, Bossaller L, De Nardo D, et al. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat Immunol. 2014;15(8):727–737.
  • Xu X, Jackson PL, Tanner S, et al. A self-propagating matrix metalloprotease-9 (MMP-9) dependent cycle of chronic neutrophilic inflammation. PLoS One. 2011;6(1):e15781.
  • Russell RE, Culpitt SV, DeMatos C, et al. Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2002;26(5):602–609.
  • Takeyama K, Fahy JV, Nadel JA. Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am J Respir Crit Care Med. 2001;163(2):511–516.
  • Pelleg A, Schulman ES, Barnes PJ. Extracellular adenosine 5'-triphosphate in obstructive airway diseases. Chest. 2016;150(4):908–915.
  • Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385(9974):1198–1205.
  • Black JL, Panettieri RA, Banerjee A, et al. Airway smooth muscle in asthma: just a target for bronchodilation?. Clin Chest Med. 2012;33(3):543–558.
  • Chung KF, Rogers DF, Barnes PJ, et al. The role of increased airway microvascular permeability and plasma exudation in asthma. Eur Respir J. 1990;3(3):329–337.
  • Persson CG, Andersson M, Greiff L, et al. Airway permeability. Clin Exp Allergy. 1995;25(9):807–814.
  • Ordonez CL, Khashayar R, Wong HH, et al. Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Respir Crit Care Med. 2001;163(2):517–523.
  • Lammers JW, Barnes PJ, Chung KF. Nonadrenergic, non-cholinergic airway inhibitory nerves. Eur Respir J. 1992;5:239–246.
  • Ollerenshaw SL, Jarvis D, Sullivan CE, et al. Substance P immunoreactive nerves in airways from asthmatics and non-asthmatics. Eur Respir J. 1991;4:673–682.
  • Barnes PJ. Modulation of neurotransmission in airways. Physiol Rev. 1992;72(3):699–729.
  • James AL, Maxwell PS, Pearce-Pinto G, et al. The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am J Respir Crit Care Med. 2002;166(12):1590–1595.
  • Chetta A, Foresi A, Del Donno M, et al. Airways remodeling is a distinctive feature of asthma and is related to severity of disease. Chest. 1997;111(4):852–857.
  • Cazzola M, Page CP, Rogliani P, et al. β2-agonist therapy in lung disease. Am J Respir Crit Care Med. 2013;187(7):690–696.
  • Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev. 2004;3:CD003269.
  • Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367(13):1198–1207.
  • Newman S, Salmon A, Nave R, et al. High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma. Respir Med. 2006;100:375–384.
  • Barnes PJ. Inhaled corticosteroids. Pharmaceuticals (Basel). 2010;3:514–540.
  • Bisgaard H. Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma. Allergy. 2001;56(s66):7–11.
  • Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma A randomized, controlled trial Montelukast/Beclomethasone Study Group. Ann Intern Med. 1999;130(6):487–495.
  • Nelson HS, Busse WW, Kerwin E, et al. Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol. 2000;106(6):1088–1095.
  • Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011;154:573–582.
  • Holgate ST, Djukanovic R, Casale T, et al. Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin Exp Allergy. 2005;35(4):408–416.
  • Barnes PJ. Theophylline. Am J Respir Crit Care Med. 2013;188(8):901–906.
  • Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108(2):184–190.
  • Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy Eur J Allergy Clin Immunol. 2005;60(3):309–316.
  • Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651–659.
  • Bel EH, Wenzel SE, Thompson PJ, SIRIUS Investigators, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–1197.
  • Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–1207.
  • Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–366.
  • Corren J, Weinstein S, Janka L, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150(4):799–810.
  • Bjermer L, Lemiere C, Maspero J, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150(4):789–798.
  • FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128–2141.
  • Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting b2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115–2127.
  • Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid–sparing effect of Benralizumab in severe asthma. N Engl J Med. 2017;376(25):2448–2458.
  • Castro M, Castro J, Pavord I, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486–2496.
  • Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid dependent severe asthma. N Engl J Med. 2018;378(26):2475–2785.
  • Howell JB, Altounyan RE. A double-blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma. Lancet. 1967;2(7515):539–542.
  • Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;8:CD001186.
  • Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest. 2008;118(11):3546–3556.
  • Sempowski GD, Beckmann MP, Derdak S, et al. Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors: role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. J Immunol. 1994;152:3606–3614.
  • Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31–44.
  • Antoniu SA, Cojocaru I. Pitrakinra for asthma. Expert Opin Biol Ther. 2010;10:1609–1615.
  • Wenzel S, Wilbraham D, Fuller R, et al. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007;370(9596):1422–1431.
  • Hart TK, Blackburn MN, Brigham-Burke M, et al. Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol. 2002;130(1):93–100.
  • Pelaia G, Vatrella A, Maselli R. The potential of biologics for the treatment of asthma. Nat Rev Drug Discov. 2012;11(12):958–972.
  • Steinke JW. Anti-interleukin-4 therapy. Immunol Allergy Clin North Am. 2004;24:599–614, vi.
  • Ortega HG, Yancey SW, Mayer B, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;4(7):549–556.
  • Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017;5(5):390–400.
  • Li J, Wang F, Lin C, et al. The efficacy and safety of reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: a systematic review and meta-analysis. J Asthma. 2017;54(3):300–307.
  • Santus P, Ferrando M, Baiardini I, et al. Patients beliefs on intravenous and subcutaneous routes of administration of biologics for severe asthma treatment: a cross-sectional observational survey study. World Allergy Organ J. 2019;12(4):100030.
  • Chapman RW, Phillips JE, Hipkin RW, et al. CXCR2 antagonists for the treatment of pulmonary disease. Pharmacol Ther. 2009;121:55–68.
  • Chapman RW, Minnicozzi M, Celly CS, et al. A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet70 cell hyperplasia in animal models of pulmonary inflammation. J Pharmacol Exp Ther. 2007;322(2):486–493.
  • Nair P, Gaga M, Zervas E, on behalf of the study investigators, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2012;42(7):1097–1103.
  • O'Byrne PM, Metev H, Puu M, et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4(10):797–806.
  • Gallelli L, Busceti MT, Vatrella A, et al. Update on anticytokine treatment for asthma. Biomed Res Int. 2013;2013:104315.
  • Zhou Y, McLane M, Levitt RC. Th2 cytokines and asthma. Interleukin-9 as a therapeutic target for asthma. Respir Res. 2001;2(2):80–84.
  • Oh CK, Leigh R, McLaurin KK, Kim K, et al. A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir Res. 2013;14:93.
  • Parker JM, Oh CK, LaForce C, MEDI-528 Clinical Trials Group, et al. Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma. BMC Pulm Med. 2011;11:14.
  • Walsh GM. Tralokinumab, an anti-IL-13 mAb for the potential treatment of asthma and COPD. Curr Opin Investig Drugs. 2010;11(11):1305–1312.
  • Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365(12):1088–1098.
  • Hanania NA, Korenblat P, Chapman KR, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med. 2016;4(10):781–796.
  • Brightling CE, Chanez P, Leigh R, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo controlled, phase 2b trial. Lancet Respir Med. 2015;3(9):692–701.
  • van HB, Nnane IP, Bouman-Thio E, et al. Safety, tolerability and pharmacokinetics of a human anti-interleukin-13 monoclonal antibody (CNTO 5825) in an ascending single-dose first-in-human study . Br J Clin Pharmacol. 2013;75:1289–1298.
  • Hodsman P, Ashman C, Cahn A, et al. A phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 monoclonal antibody in healthy subjects and mild asthmatics. Br J Clin Pharmacol. 2013;75:118–128.
  • Fogli LK, Sundrud MS, Goel S, et al. T cell-derived IL-17 mediates epithelial changes in the airway and drives pulmonary neutrophilia. J Immunol. 2013;191(6):3100–3111.
  • 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(5):1185–1187.
  • Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of Brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188:1294–1302.
  • Kirsten A, Watz H, Pedersen F, et al. The anti-IL-17A antibody secukinumab does not attenuate ozone-induced airway neutrophilia in healthy volunteers. Eur Respir J. 2013;41(1):239–241.
  • Clinical trials.gov (Accessed on 7 August 2018).
  • Kouzaki H, Tojima I, Kita H, et al. Transcription of interleukin-25 and extracellular release of the protein is regulated by allergen proteases in airway epithelial cells. Am J Respir Cell Mol Biol. 2013;49(5):741–750.
  • Hurst SD, Muchamuel T, Gorman D, et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol. 2002;169(1):443–453.
  • Lee JU, Chang HS, Lee HJ, et al. Association of interleukin-25 levels with development of aspirin induced respiratory diseases. Respir Med. 2017;123:71–78.
  • Cully M. Lung disease: IL-25 blockade could reduce virus-associated asthma attacks. Nat Rev Drug Discov. 2014;13(11):810–811.
  • Tang W, Smith SG, Beaudin S, et al. IL-25 and IL-25 receptor expression on eosinophils from subjects with allergic asthma. Int Arch Allergy Immunol. 2014;163(1):5–10.
  • Cheng D, Xue Z, Yi L, et al. Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma. Am J Respir Crit Care Med. 2014;190(6):639–648.
  • Mitchell PD, O'Byrne PM. Epithelial-derived cytokines in asthma. Chest. 2017;151:1338–1344.
  • Smith SG, Chen R, Kjarsgaard M, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016;137(1):75–86.
  • Kamijo S, Takeda H, Tokura T, et al. IL-33-mediated innate response and adaptive immune cells contribute to maximum responses of protease allergen-induced allergic airway inflammation. J Immunol. 2013;190(9):4489–4499.
  • Han H, Ziegler SF. Intradermal administration of IL-33 induces allergic airway inflammation. Sci Rep. 2017;7(1):8.
  • Mizutani N, Nabe T, Yoshino S. Interleukin-33 and alveolar macrophages contribute to the mechanisms underlying the exacerbation of IgE-mediated airway inflammation and remodelling in mice. Immunology. 2013;139:205–218.
  • Préfontaine D, Lajoie-Kadoch S, Foley S, et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol. 2009;183(8):5094–5103.
  • Ziegler AF. The biology of thymic stromal lymphopoietin (TSLP). San Diego: Elsevier; 2013.
  • Ying S, O'Connor B, Ratoff J, et al. Expression and cellular provenance of thymic stromal Lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. 2008;181(4):2790–2708.
  • Harada M, Hirota T, Jodo AI, et al. Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma. Am J Respir Cell Mol Biol. 2011;44(6):787–793.
  • Gauvreau GM, O'Byrne PM, Boulet L-P, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014;370(22):2102–2110.
  • Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377(10):936–946.
  • Licari A, Marseglia G, Castagnoli R, et al. The discovery and development of omalizumab for the treatment of asthma. Expert Opin Drug Discov. 2015;10(9):1033–1042.
  • Humbert M, Busse W, Hanania NA, et al. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract. 2014;2(5):525–536.
  • Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;13:CD003559.
  • Canonica GW, Rottoli P, Bucca C, et al. Improvement of patient-reported outcomes in severe allergic asthma by omalizumab treatment: the real life observational PROXIMA study. World Allergy Organ J. 2018;11:33.
  • Gauvreau GM, Arm JP, Boulet LP, et al. Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses. J Allergy Clin Immunol. 2016;138(4):1051–1059.
  • Harris JM, Maciuca R, Bradley MS, et al. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. Respir Res. 2016;17:29.
  • Farne H, Jackson DJ, Johnston SL. Are emerging PGD2 antagonists a promising therapy class for treating asthma?. Expert Opin Emerg Drugs. 2016;21(4):359–364.
  • Pettipher R, Hunter MG, Perkins CM, et al. Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459. Allergy. 2014;69(9):1223–1232.
  • Wenzel S, Hopkins R, Saunders M, et al. Safety and efficacy of ARRY-502, a potent, selective, Oral CRTh2 antagonist, in patients with mild to moderate Th2-driven asthma. J Allergy Clin Immunol. 2014;133(2):AB4.
  • Hall IP, Fowler AV, Gupta A, et al. Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment. Pulm Pharmacol Ther. 2015;32:37–44.
  • Erpenbeck VJ, Popov TA, Miller D, et al. The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma. Pulm Pharmacol Ther. 2016;39:54–63.
  • Singh D, Cadden P, Hunter M, et al. Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. Eur Respir J. 2013;41(1):46–52.
  • Bain G, King CD, Brittain J, et al. Pharmacodynamics, pharmacokinetics, and safety of AM211: a novel and potent antagonist of the prostaglandin D2 receptor type 2. J Clin Pharmacol. 2012;52:1482–1493.
  • Sandham DA, Arnold N, Aschauer H, et al. Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases. Bioorg Med Chem. 2013;21:6582–6591.
  • Fretz H, Valdenaire A, Pothier J, et al. Identification of 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (setipiprant/ACT-129968), a potent, selective, and orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonist. J Med Chem. 2013;56:4899–4911.
  • Busse WW, Wenzel SE, Meltzer EO, et al. Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients. J Allergy Clin Immunol. 2013;131:339–345.
  • Garn H, Renz H. GATA-3-specific DNAzyme - a novel approach for stratified asthma therapy . Eur J Immunol. 2017;47(1):22–30.
  • Krug N, Hohlfeld JM, Kirsten AM, et al. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med. 2015;372(21):1987–1995.
  • Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006;354:697–708.
  • Lukacs NW, Strieter RM, Chensue SW, et al. TNF-alpha mediates recruitment of neutrophils and eosinophils during airway inflammation. J Immunol. 1995;154:5411–5417.
  • Erin EM, Leaker BR, Nicholson GC, et al. The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am J Respir Crit Care Med. 2006;174(7):753–762.
  • Morjaria JB, Chauhan AJ, Babu KS, et al. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax. 2008;63:584–591.
  • Holgate ST, Noonan M, Chanez P, et al. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J. 2011;37(6):1352–1359.
  • Wenzel SE, Barnes PJ, Bleecker ER, T03 Asthma Investigators, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med. 2009;179(7):549–558.
  • Banner KH, Igney F, Poll C. TRP channels: emerging targets for respiratory disease. Pharmacol Ther. 2011;130(3):371–384.
  • Shapiro D, Deering-Rice CE, Romero EG, et al. Activation of transient receptor potential ankyrin-1 (TRPA1) in lung cells by wood smoke particulate material. Chem Res Toxicol. 2013;26(5):750–758.
  • Raemdonck K, de Alba J, Birrell MA, et al. A role for sensory nerves in the late asthmatic response. Thorax. 2012;67:19–25.
  • Andre E, Campi B, Materazzi S, et al. Cigarette smoke-induced neurogenic inflammation is mediated by alpha- beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J Clin Invest. 2008;118:2574–2782.
  • Hox V, Vanoirbeek JA, Alpizar YA, et al. Crucial role of transient receptor potential ankyrin 1 and mast cells in induction of nonallergic airway hyperreactivity in mice. Am J Respir Crit Care Med. 2013;187(5):486–493.
  • Caceres AI, Brackmann M, Elia MD, et al. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc Natl Acad Sci USA. 2009;106(22):9099–9104.
  • Spiess PC, Kasahara D, Habibovic A, et al. Acrolein exposure suppresses antigen-induced pulmonary inflammation. Respir Res. 2013;14:107.
  • Rehman R, Bhat YA, Panda L, et al. TRPV1 inhibition attenuates IL-13 mediated asthma features in mice by reducing airway epithelial injury. Int Immunopharmacol. 2013;15:597–605.
  • Duan W, Wong WS. Targeting mitogen-activated protein kinases for asthma. Curr Drug Targets. 2006;7:691–698.
  • Underwood DC, Osborn RR, Kotzer CJ, et al. SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence. J Pharmacol Exp Ther. 2000;293:281–288.
  • Liang L, Li F, Bao A, et al. Activation of p38 mitogen activated protein kinase in ovalbumin and ozone-induced mouse model of asthma. Respirol. 2013;18:20–29.
  • Duan W, Chan JH, Wong CH, et al. Anti-inflammatory effects of mitogen-activated protein kinase inhibitor U0126 in an asthma mouse model. J Immunol. 2004;172(11):7053–7059.
  • Mir-Kasimov M, Sturrock A, McManus M, et al. Effect of alveolar epithelial cell plasticity on the regulation of GM-CSF expression. Am J Physiol Lung Cell Mol Physiol. 2012;302:L504–L511.
  • Holgate ST, Roberts G, Arshad HS, et al. The role of the airway epithelium and its interaction with environmental factors in asthma pathogenesis. Proc Am Thorac Soc. 2009;6:655–659.
  • Krinner EM, Raum T, Petsch S, et al. A human monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF. Mol Immunol. 2007;44:916–925.
  • Alkhouri H, Moir LM, Armour CL, et al. CXCL1 is a negative regulator of mast cell chemotaxis to airway smooth muscle cell products in vitro. Clin Exp Allergy. 2014;44(3):381–392.
  • Neighbour H, Boulet LP, Lemiere C, et al. Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2014;44(4):508–516.
  • Cahn A, Hodgson S, Wilson R, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol. 2013;14:14.
  • Subramaniam JM, Whiteside G, McKeage K, et al. Mogamulizumab: first global approval. Drugs. 2012;72(9):1293–1298.

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