The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
권호 표지
DOI QR코드

DOI QR Code

Recent Advances in Mechanisms and Treatments of Airway Remodeling in Asthma: A Message from the Bench Side to the Clinic

  • Cho, Jae-Youn (Division of Allergy/Immunology, University of California San Diego School of Medicine)
  • Published : 2011.12.01
⟨ Previous Next ⟩

Abstract

Airway remodeling in asthma is a result of persistent inflammation and epithelial damage in response to repetitive injury. Recent studies have identified several important mediators associated with airway remodeling in asthma, including transforming growth factor-${\beta}$, interleukin (IL)-5, basic fibroblast growth factor, vascular endothelial growth factor, LIGHT, tumor necrosis factor (TNF)-${\alpha}$, thymic stromal lymphopoietin, IL-33, and IL-25. In addition, the epithelium mesenchymal transformation (EMT) induced by environmental factors may play an important role in initiating this process. Diagnostic methods using sputum and blood biomarkers as well as radiological interventions have been developed to distinguish between asthma sub-phenotypes. Human clinical trials have been conducted to evaluate biological therapies that target individual inflammatory cells or mediators including anti IgE, anti IL-5, and anti TNF-${\alpha}$. Furthermore, new drugs such as c-kit/platelet-derived growth factor receptor kinase inhibitors, endothelin-1 receptor antagonists, calcium channel inhibitors, and HMG-CoA reductase inhibitors have been developed to treat asthma-related symptoms. In addition to targeting specific inflammatory cells or mediators, preventing the initiation of EMT may be important for targeted treatment. Interestingly, bronchial thermoplasty reduces smooth muscle mass in patients with severe asthma and improves asthma-specific quality of life, particularly by reducing severe exacerbation and healthcare use. A wide range of different therapeutic approaches has been developed to address the immunological processes of asthma and to treat this complex chronic illness. An important future direction may be to investigate the role of mediators involved in the development of airway remodeling to enhance asthma therapy.

Keywords

References

  1. Broide DH. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling. J Allergy Clin Immunol 2008;121:560-570. https://doi.org/10.1016/j.jaci.2008.01.031
  2. Mauad T, Bel EH, Sterk PJ. Asthma therapy and airway remodeling. J Allergy Clin Immunol 2007;120:997-1009. https://doi.org/10.1016/j.jaci.2007.06.031
  3. 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. https://doi.org/10.1016/j.jaci.2005.07.011
  4. Cho JY, Miller M, Baek KJ, et al. Inhibition of airway remodeling in IL-5-deficient mice. J Clin Invest 2004;113:551-560. https://doi.org/10.1172/JCI19133
  5. Humbles AA, Lloyd CM, McMillan SJ, et al. A critical role for eosinophils in allergic airways remodeling. Science 2004;305:1776-1779. https://doi.org/10.1126/science.1100283
  6. Fulkerson PC, Fischetti CA, McBride ML, Hassman LM, Hogan SP, Rothenberg ME. A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation. Proc Natl Acad Sci U S A 2006;103:16418-16423. https://doi.org/10.1073/pnas.0607863103
  7. Doherty TA, Soroosh P, Khorram N, et al. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nat Med 2011;17:596-603. https://doi.org/10.1038/nm.2356
  8. Cho JY, Pham A, Rosenthal P, Miller M, Doherty T, Broide DH. Chronic OVA allergen challenged TNF p55/p75 receptor deficient mice have reduced airway remodeling. Int Immunopharmacol 2011;11:1038-1044. https://doi.org/10.1016/j.intimp.2011.02.024
  9. Yum HY, Cho JY, Miller M, Broide DH. Allergen-induced coexpression of bFGF and TGF-$\beta$1 by macrophages in a mouse model of airway remodeling: bFGF induces macrophage TGF-$\beta$1 expression in vitro. Int Arch Allergy Immunol 2011;155:12-22.
  10. Holgate ST, Davies DE, Lackie PM, Wilson SJ, Puddicombe SM, Lordan JL. Epithelial-mesenchymal interactions in the pathogenesis of asthma. J Allergy Clin Immunol 2000;105(2 Pt 1):193-204. https://doi.org/10.1016/S0091-6749(00)90066-6
  11. Holgate ST, Arshad HS, Roberts GC, Howarth PH, Thurner P, Davies DE. A new look at the pathogenesis of asthma. Clin Sci (Lond) 2009;118:439-450. https://doi.org/10.1042/CS20090474
  12. Wang YH, Liu YJ. Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy 2009;39:798-806. https://doi.org/10.1111/j.1365-2222.2009.03241.x
  13. Jacquet A. Interactions of airway epithelium with protease allergens in the allergic response. Clin Exp Allergy 2011;41:305-311. https://doi.org/10.1111/j.1365-2222.2010.03661.x
  14. Rothenberg ME. Eosinophilia. N Engl J Med 1998;338:1592-1600. https://doi.org/10.1056/NEJM199805283382206
  15. Lopez AF, Sanderson CJ, Gamble JR, Campbell HD, Young IG, Vadas MA. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J Exp Med 1988;167:219-224. https://doi.org/10.1084/jem.167.1.219
  16. 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;112:1029-1036. https://doi.org/10.1172/JCI17974
  17. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984. https://doi.org/10.1056/NEJMoa0808991
  18. Wegmann M, Goggel R, Sel S, et al. Effects of a low-molecularweight CCR-3 antagonist on chronic experimental asthma. Am J Respir Cell Mol Biol 2007;36:61-67. https://doi.org/10.1165/rcmb.2006-0188OC
  19. Komai M, Tanaka H, Nagao K, et al. A novel CC-chemokine receptor 3 antagonist, Ki19003, inhibits airway eosinophilia and subepithelial/peribronchial fibrosis induced by repeated antigen challenge in mice. J Pharmacol Sci 2010;112:203-213. https://doi.org/10.1254/jphs.09277FP
  20. Tateno H, Crocker PR, Paulson JC. Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs that are selectively expressed on eosinophils and recognize 6'-sulfo-sialyl Lewis X as a preferred glycan ligand. Glycobiology 2005;15:1125-1135. https://doi.org/10.1093/glycob/cwi097
  21. Bochner BS, Alvarez RA, Mehta P, et al. Glycan array screening reveals a candidate ligand for Siglec-8. J Biol Chem 2005;280:4307-4312. https://doi.org/10.1074/jbc.M412378200
  22. Song DJ, Cho JY, Lee SY, et al. Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling. J Immunol 2009;183:5333-5341. https://doi.org/10.4049/jimmunol.0801421
  23. Cho JY, Song DJ, Pham A, et al. Chronic OVA allergen challenged Siglec-F deficient mice have increased mucus, remodeling, and epithelial Siglec-F ligands which are up-regulated by IL-4 and IL-13. Respir Res 2010;11:154. https://doi.org/10.1186/1465-9921-11-154
  24. Luzina IG, Atamas SP, Wise R, et al. Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients. Arthritis Rheum 2003;48:2262-2274. https://doi.org/10.1002/art.11080
  25. Halwani R, Al-Muhsen S, Al-Jahdali H, Hamid Q. Role of transforming growth factor-$\beta$ in airway remodeling in asthma. Am J Respir Cell Mol Biol 2011;44:127-133. https://doi.org/10.1165/rcmb.2010-0027TR
  26. Yanai M, Sekizawa K, Ohrui T, Sasaki H, Takishima T. Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J Appl Physiol 1992;72:1016-1023. https://doi.org/10.1152/jappl.1992.72.3.1016
  27. McMillan SJ, Xanthou G, Lloyd CM. Manipulation of allergeninduced airway remodeling by treatment with anti-TGF-beta antibody: effect on the Smad signaling pathway. J Immunol 2005;174:5774-5780. https://doi.org/10.4049/jimmunol.174.9.5774
  28. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 2007;117:524-529. https://doi.org/10.1172/JCI31487
  29. Le AV, Cho JY, Miller M, McElwain S, Golgotiu K, Broide DH. Inhibition of allergen-induced airway remodeling in Smad 3-deficient mice. J Immunol 2007;178:7310-7316. https://doi.org/10.4049/jimmunol.178.11.7310
  30. Gregory LG, Mathie SA, Walker SA, Pegorier S, Jones CP, Lloyd CM. 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;182:143-154. https://doi.org/10.1164/rccm.200905-0725OC
  31. Redington AE, Madden J, Frew AJ, et al. Transforming growth factor-beta 1 in asthma: measurement in bronchoalveolar lavage fluid. Am J Respir Crit Care Med 1997;156:642-647. https://doi.org/10.1164/ajrccm.156.2.9605065
  32. Chakir J, Shannon J, Molet S, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol 2003;111:1293-1298. https://doi.org/10.1067/mai.2003.1557
  33. Girodet PO, Ozier A, Bara I, Tunon de Lara JM, Marthan R, Berger P. Airway remodeling in asthma: new mechanisms and potential for pharmacological intervention. Pharmacol Ther 2011;130:325-337. https://doi.org/10.1016/j.pharmthera.2011.02.001
  34. Bosse Y, Rola-Pleszczynski M. FGF2 in asthmatic airwaysmooth- muscle-cell hyperplasia. Trends Mol Med 2008;14:3-11. https://doi.org/10.1016/j.molmed.2007.11.003
  35. Bosse Y, Thompson C, Stankova J, Rola-Pleszczynski M. Fibroblast growth factor 2 and transforming growth factor beta1 synergism in human bronchial smooth muscle cell proliferation. Am J Respir Cell Mol Biol 2006;34:746-753. https://doi.org/10.1165/rcmb.2005-0309OC
  36. Strutz F, Zeisberg M, Renziehausen A, et al. TGF-beta 1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2). Kidney Int 2001;59:579-592. https://doi.org/10.1046/j.1523-1755.2001.059002579.x
  37. Qu Z, Kayton RJ, Ahmadi P, et al. Ultrastructural immunolocalization of basic fibroblast growth factor in mast cell secretory granules: morphological evidence for bfgf release through degranulation. J Histochem Cytochem 1998;46:1119-1128. https://doi.org/10.1177/002215549804601004
  38. Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000;7:165-197. https://doi.org/10.1677/erc.0.0070165
  39. Bosse Y, Stankova J, Rola-Pleszczynski M. Transforming growth factor-beta1 in asthmatic airway smooth muscle enlargement: is fibroblast growth factor-2 required? Clin Exp Allergy 2010;40:710-724. https://doi.org/10.1111/j.1365-2222.2010.03497.x
  40. Cho SH, Yao Z, Wang SW, et al. Regulation of activin A expression in mast cells and asthma: its effect on the proliferation of human airway smooth muscle cells. J Immunol 2003;170:4045-4052. https://doi.org/10.4049/jimmunol.170.8.4045
  41. Jeon SG, Lee CG, Oh MH, et al. Recombinant basic fibroblast growth factor inhibits the airway hyperresponsiveness, mucus production, and lung inflammation induced by an allergen challenge. J Allergy Clin Immunol 2007;119:831-837. https://doi.org/10.1016/j.jaci.2006.12.653
  42. Kanazawa H, Yoshikawa T. Up-regulation of thrombin activity induced by vascular endothelial growth factor in asthmatic airways. Chest 2007;132:1169-1174. https://doi.org/10.1378/chest.07-0945
  43. Redington AE, Roche WR, Madden J, et al. Basic fibroblast growth factor in asthma: measurement in bronchoalveolar lavage fluid basally and following allergen challenge. J Allergy Clin Immunol 2001;107:384-387. https://doi.org/10.1067/mai.2001.112268
  44. Clauss M. Functions of the VEGF receptor-1 (FLT-1) in the vasculature. Trends Cardiovasc Med 1998;8:241-245. https://doi.org/10.1016/S1050-1738(98)00015-2
  45. Charan NB, Baile EM, Pare PD. Bronchial vascular congestion and angiogenesis. Eur Respir J 1997;10:1173-1180. https://doi.org/10.1183/09031936.97.10051173
  46. Antony AB, Tepper RS, Mohammed KA. Cockroach extract antigen increases bronchial airway epithelial permeability. J Allergy Clin Immunol 2002;110:589-595. https://doi.org/10.1067/mai.2002.127798
  47. 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;10:1095-1103. https://doi.org/10.1038/nm1105
  48. Bhandari V, Choo-Wing R, Chapoval SP, et al. Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung. Proc Natl Acad Sci U S A 2006;103:11021-11026. https://doi.org/10.1073/pnas.0601057103
  49. Asai K, Kanazawa H, Otani K, Shiraishi S, Hirata K, Yoshikawa J. Imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from asthmatic subjects. J Allergy Clin Immunol 2002;110:571-575. https://doi.org/10.1067/mai.2002.127797
  50. Abdel-Rahman AM, el-Sahrigy SA, Bakr SI. A comparative study of two angiogenic factors: vascular endothelial growth factor and angiogenin in induced sputum from asthmatic children in acute attack. Chest 2006;129:266-271. https://doi.org/10.1378/chest.129.2.266
  51. Bae YJ, Kim TB, Moon KA, et al. Vascular endothelial growth factor levels in induced sputum and emphysematous changes in smoking asthmatic patients. Ann Allergy Asthma Immunol 2009;103:51-56. https://doi.org/10.1016/S1081-1206(10)60143-3
  52. Costa JJ, Matossian K, Resnick MB, et al. Human eosinophils can express the cytokines tumor necrosis factor-alpha and macrophage inflammatory protein-1 alpha. J Clin Invest 1993;91:2673-2684. https://doi.org/10.1172/JCI116506
  53. Reuter S, Heinz A, Sieren M, et al. Mast cell-derived tumour necrosis factor is essential for allergic airway disease. Eur Respir J 2008;31:773-782. https://doi.org/10.1183/09031936.00058907
  54. Nakae S, Ho LH, Yu M, et al. Mast cell-derived TNF contributes to airway hyperreactivity, inflammation, and TH2 cytokine production in an asthma model in mice. J Allergy Clin Immunol 2007;120:48-55. https://doi.org/10.1016/j.jaci.2007.02.046
  55. 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. https://doi.org/10.1056/NEJMoa050580
  56. Vandenbroucke RE, Dejonckheere E, Libert C. A therapeutic role for MMP inhibitors in lung diseases? Eur Respir J 2011;38:1200-1214. https://doi.org/10.1183/09031936.00027411
  57. Lim DH, Cho JY, Miller M, McElwain K, McElwain S, Broide DH. Reduced peribronchial fibrosis in allergen-challenged MMP-9-deficient mice. Am J Physiol Lung Cell Mol Physiol 2006;291:L265-L271. https://doi.org/10.1152/ajplung.00305.2005
  58. Lee YC, Lee HB, Rhee YK, Song CH. The involvement of matrix metalloproteinase-9 in airway inflammation of patients with acute asthma. Clin Exp Allergy 2001;31:1623-1630. https://doi.org/10.1046/j.1365-2222.2001.01211.x
  59. Van Eerdewegh P, Little RD, Dupuis J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002;418:426-430. https://doi.org/10.1038/nature00878
  60. Jie Z, Jin M, Cai Y, et al. The effects of Th2 cytokines on the expression of ADAM33 in allergen-induced chronic airway inflammation. Respir Physiol Neurobiol 2009;168:289-294. https://doi.org/10.1016/j.resp.2009.07.019
  61. Foley SC, Mogas AK, Olivenstein R, et al. Increased expression of ADAM33 and ADAM8 with disease progression in asthma. J Allergy Clin Immunol 2007;119:863-871. https://doi.org/10.1016/j.jaci.2006.12.665
  62. Lloyd CM. IL-33 family members and asthma - bridging innate and adaptive immune responses. Curr Opin Immunol 2010;22:800-806. https://doi.org/10.1016/j.coi.2010.10.006
  63. Shan L, Redhu NS, Saleh A, Halayko AJ, Chakir J, Gounni AS. Thymic stromal lymphopoietin receptor-mediated IL-6 and CC/CXC chemokines expression in human airway smooth muscle cells: role of MAPKs (ERK1/2, p38, and JNK) and STAT3 pathways. J Immunol 2010;184:7134-7143. https://doi.org/10.4049/jimmunol.0902515
  64. Al-Shami A, Spolski R, Kelly J, Keane-Myers A, Leonard WJ. A role for TSLP in the development of inflammation in an asthma model. J Exp Med 2005;202:829-839. https://doi.org/10.1084/jem.20050199
  65. Zhang F, Huang G, Hu B, Song Y, Shi Y. A soluble thymic stromal lymphopoietin (TSLP) antagonist, TSLPR-immunoglobulin, reduces the severity of allergic disease by regulating pulmonary dendritic cells. Clin Exp Immunol 2011;164:256-264. https://doi.org/10.1111/j.1365-2249.2011.04328.x
  66. Heijink IH, Postma DS, Noordhoek JA, Broekema M, Kapus A. House dust mite-promoted epithelial-to-mesenchymal transition in human bronchial epithelium. Am J Respir Cell Mol Biol 2010;42:69-79. https://doi.org/10.1165/rcmb.2008-0449OC
  67. Heijink IH, van Oosterhout A, Kapus A. Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction. Eur Respir J 2010;36:1016-1026. https://doi.org/10.1183/09031936.00125809
  68. Ying S, O'Connor B, Ratoff J, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol 2005;174:8183-8190. https://doi.org/10.4049/jimmunol.174.12.8183
  69. 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;181:2790-2798. https://doi.org/10.4049/jimmunol.181.4.2790
  70. Zhou B, Comeau MR, De Smedt T, et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol 2005;6:1047-1053. https://doi.org/10.1038/ni1247
  71. Owyang AM, Zaph C, Wilson EH, et al. Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. J Exp Med 2006;203:843-849. https://doi.org/10.1084/jem.20051496
  72. Angkasekwinai P, Park H, Wang YH, et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J Exp Med 2007;204:1509-1517. https://doi.org/10.1084/jem.20061675
  73. Fort MM, Cheung J, Yen D, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 2001;15:985-995. https://doi.org/10.1016/S1074-7613(01)00243-6
  74. Hurst SD, Muchamuel T, Gorman DM, 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;169:443-453. https://doi.org/10.4049/jimmunol.169.1.443
  75. Corrigan CJ, Wang W, Meng Q, et al. T-helper cell type 2 (Th2) memory T cell-potentiating cytokine IL-25 has the potential to promote angiogenesis in asthma. Proc Natl Acad Sci U S A 2011;108:1579-1584. https://doi.org/10.1073/pnas.1014241108
  76. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1- like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005;23:479-490. https://doi.org/10.1016/j.immuni.2005.09.015
  77. Sanada S, Hakuno D, Higgins LJ, Schreiter ER, McKenzie AN, Lee RT. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest 2007;117:1538-1549. https://doi.org/10.1172/JCI30634
  78. Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL- 33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One 2008;3:e3331. https://doi.org/10.1371/journal.pone.0003331
  79. Wood IS, Wang B, Trayhurn P. IL-33, a recently identified interleukin- 1 gene family member, is expressed in human adipocytes. Biochem Biophys Res Commun 2009;384:105-109. https://doi.org/10.1016/j.bbrc.2009.04.081
  80. Kurowska-Stolarska M, Stolarski B, Kewin P, et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J Immunol 2009;183:6469-6477. https://doi.org/10.4049/jimmunol.0901575
  81. Kondo Y, Yoshimoto T, Yasuda K, et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol 2008;20:791-800. https://doi.org/10.1093/intimm/dxn037
  82. Zhiguang X, Wei C, Steven R, et al. Over-expression of IL- 33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic mice. Immunol Lett 2010;131:159-165. https://doi.org/10.1016/j.imlet.2010.04.005
  83. Liu X, Li M, Wu Y, Zhou Y, Zeng L, Huang T. Anti-IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthma. Biochem Biophys Res Commun 2009;386:181-185. https://doi.org/10.1016/j.bbrc.2009.06.008
  84. Coyle AJ, Lloyd C, Tian J, et al. Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. J Exp Med 1999;190:895-902. https://doi.org/10.1084/jem.190.7.895
  85. Rankin AL, Mumm JB, Murphy E, et al. IL-33 induces IL-13- dependent cutaneous fibrosis. J Immunol 2010;184:1526-1535. https://doi.org/10.4049/jimmunol.0903306
  86. Prefontaine D, Nadigel J, Chouiali F, et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J Allergy Clin Immunol 2010;125:752-754. https://doi.org/10.1016/j.jaci.2009.12.935
  87. Smith DE. IL-33: a tissue derived cytokine pathway involved in allergic inf lammation and asthma. Clin Exp Allergy 2010;40:200-208. https://doi.org/10.1111/j.1365-2222.2009.03384.x
  88. Rasmussen F, Taylor DR, Flannery EM, et al. Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/vital capacity ratio: a longitudinal population study from childhood to adulthood. Am J Respir Crit Care Med 2002;165:1480-1488. https://doi.org/10.1164/rccm.2108009
  89. Mitsunobu F, Tanizaki Y. The use of computed tomography to assess asthma severity. Curr Opin Allergy Clin Immunol 2005;5:85-90. https://doi.org/10.1097/00130832-200502000-00015
  90. Gupta S, Siddiqui S, Haldar P, et al. Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes. Thorax 2010;65:775-781. https://doi.org/10.1136/thx.2010.136374
  91. Aysola R, de Lange EE, Castro M, Altes TA. Demonstration of the heterogeneous distribution of asthma in the lungs using CT and hyperpolarized helium-3 MRI. J Magn Reson Imaging 2010;32:1379-1387. https://doi.org/10.1002/jmri.22388
  92. de Lange EE, Altes TA, Patrie JT, et al. Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry. Chest 2006;130:1055-1062. https://doi.org/10.1378/chest.130.4.1055
  93. Fain SB, Gonzalez-Fernandez G, Peterson ET, et al. Evaluation of structure-function relationships in asthma using multidetector CT and hyperpolarized He-3 MRI. Acad Radiol 2008;15:753-762. https://doi.org/10.1016/j.acra.2007.10.019
  94. Delimpoura V, Bakakos P, Tseliou E, et al. Increased levels of osteopontin in sputum supernatant in severe refractory asthma. Thorax 2010;65:782-786. https://doi.org/10.1136/thx.2010.138552
  95. Broekema M, Timens W, Vonk JM, et al. Persisting remodeling and less airway wall eosinophil activation in complete remission of asthma. Am J Respir Crit Care Med 2011;183:310-316. https://doi.org/10.1164/rccm.201003-0494OC
  96. Wang K, Liu CT, Wu YH, et al. Effects of formoterol-budesonide on airway remodeling in patients with moderate asthma. Acta Pharmacol Sin 2011;32:126-132. https://doi.org/10.1038/aps.2010.170
  97. Palikhe NS, Kim JH, Park HS. Biomarkers predicting isocyanate- induced asthma. Allergy Asthma Immunol Res 2011;3:21-26. https://doi.org/10.4168/aair.2011.3.1.21
  98. Soja J, Grzanka P, Sladek K, et al. The use of endobronchial ultrasonography in assessment of bronchial wall remodeling in patients with asthma. Chest 2009;136:797-804. https://doi.org/10.1378/chest.08-2759
  99. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol 2005;115:459-465. https://doi.org/10.1016/j.jaci.2004.11.053
  100. Rabe KF, Calhoun WJ, Smith N, Jimenez P. Can anti-IgE therapy prevent airway remodeling in allergic asthma? Allergy 2011;66:1142-1151. https://doi.org/10.1111/j.1398-9995.2011.02617.x
  101. van Rensen EL, Evertse CE, van Schadewijk WA, et al. Eosinophils in bronchial mucosa of asthmatics after allergen challenge: effect of anti-IgE treatment. Allergy 2009;64:72-80. https://doi.org/10.1111/j.1398-9995.2008.01881.x
  102. Holgate S, Smith N, Massanari M, Jimenez P. Effects of omalizumab on markers of inflammation in patients with allergic asthma. Allergy 2009;64:1728-1736. https://doi.org/10.1111/j.1398-9995.2009.02201.x
  103. Kang JY, Kim JW, Kim JS, et al. Inhibitory effects of anti-immunoglobulin E antibodies on airway remodeling in a murine model of chronic asthma. J Asthma 2010;47:374-380. https://doi.org/10.3109/02770901003801972
  104. Corren J. Cytokine inhibition in severe asthma: current knowledge and future directions. Curr Opin Pulm Med 2011;17:29-33. https://doi.org/10.1097/MCP.0b013e3283413105
  105. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;360:985-993. https://doi.org/10.1056/NEJMoa0805435
  106. Gruenberg D, Busse W. Biologic therapies for asthma. Curr Opin Pulm Med 2010;16:19-24. https://doi.org/10.1097/MCP.0b013e3283328398
  107. 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;37:1352-1359. https://doi.org/10.1183/09031936.00063510
  108. 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;174:753-762. https://doi.org/10.1164/rccm.200601-072OC
  109. Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double- blind, placebo-controlled study of tumor necrosis factoralpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009;179:549-558. https://doi.org/10.1164/rccm.200809-1512OC
  110. Borish LC, Nelson HS, Corren J, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 2001;107:963-970. https://doi.org/10.1067/mai.2001.115624
  111. 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;130:93-100. https://doi.org/10.1046/j.1365-2249.2002.01973.x
  112. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. 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;370:1422-1431. https://doi.org/10.1016/S0140-6736(07)61600-6
  113. Corren J, Busse W, Meltzer EO, et al. A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma. Am J Respir Crit Care Med 2010;181:788-796. https://doi.org/10.1164/rccm.200909-1448OC
  114. Busse WW, Israel E, Nelson HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med 2008;178:1002-1008. https://doi.org/10.1164/rccm.200708-1200OC
  115. Berlin AA, Hogaboam CM, Lukacs NW. Inhibition of SCF attenuates peribronchial remodeling in chronic cockroach allergeninduced asthma. Lab Invest 2006;86:557-565. https://doi.org/10.1038/labinvest.3700419
  116. Humbert M, de Blay F, Garcia G, et al. Masitinib, a c-kit/ PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics. Allergy 2009;64:1194-1201. https://doi.org/10.1111/j.1398-9995.2009.02122.x
  117. Dube J, Chakir J, Dube C, Grimard Y, Laviolette M, Boulet LP. Synergistic action of endothelin (ET)-1 on the activation of bronchial fibroblast isolated from normal and asthmatic subjects. Int J Exp Pathol 2000;81:429-437.
  118. Taille C, Guenegou A, Almolki A, et al. ETB receptor polymorphism is associated with airway obstruction. BMC Pulm Med 2007;7:5. https://doi.org/10.1186/1471-2466-7-5
  119. Zhu G, Carlsen K, Carlsen KH, et al. Polymorphisms in the endothelin-1 (EDN1) are associated with asthma in two populations. Genes Immun 2008;9:23-29. https://doi.org/10.1038/sj.gene.6364441
  120. Trian T, Benard G, Begueret H, et al. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med 2007;204:3173-3181. https://doi.org/10.1084/jem.20070956
  121. Menzies D, Nair A, Meldrum KT, Fleming D, Barnes M, Lipworth BJ. Simvastatin does not exhibit therapeutic antiinf lammatory effects in asthma. J Allergy Clin Immunol 2007;119:328-335. https://doi.org/10.1016/j.jaci.2006.10.014
  122. Hothersall EJ, Chaudhuri R, McSharry C, et al. Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma. Thorax 2008;63:1070-1075. https://doi.org/10.1136/thx.2008.100198
  123. Danek CJ, Lombard CM, Dungworth DL, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol 2004;97:1946-1953. https://doi.org/10.1152/japplphysiol.01282.2003
  124. Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest 2005;127:1999-2006. https://doi.org/10.1378/chest.127.6.1999
  125. Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006;173:965-969. https://doi.org/10.1164/rccm.200507-1162OC
  126. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;356:1327-1337. https://doi.org/10.1056/NEJMoa064707
  127. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010;181:116-124. https://doi.org/10.1164/rccm.200903-0354OC
  128. Castro M, Rubin A, Laviolette M, et al. Persistence of effectiveness of bronchial thermoplasty in patients with severe asthma. Ann Allergy Asthma Immunol 2011;107:65-70. https://doi.org/10.1016/j.anai.2011.03.005
  129. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med 2011;11:8. https://doi.org/10.1186/1471-2466-11-8

Cited by

  1. trans -Caryophyllene, a Natural Sesquiterpene, Causes Tracheal Smooth Muscle Relaxation through Blockade of Voltage-Dependent Ca 2+ Channels vol.17, pp.10, 2011, https://doi.org/10.3390/molecules171011965
  2. Predicting adverse drug reaction profiles by integrating protein interaction networks with drug structures vol.13, pp.2, 2011, https://doi.org/10.1002/pmic.201200337
  3. AVE 0991, a non-peptide mimic of angiotensin-(1-7) effects, attenuates pulmonary remodelling in a model of chronic asthma : Mas agonist prevents asthma pulmonary remodelling vol.170, pp.4, 2013, https://doi.org/10.1111/bph.12318
  4. Immune response to Streptococcus pneumoniae in asthma patients: comparison between stable situation and exacerbation vol.173, pp.1, 2011, https://doi.org/10.1111/cei.12082
  5. Eosinophils Promote Epithelial to Mesenchymal Transition of Bronchial Epithelial Cells vol.8, pp.5, 2013, https://doi.org/10.1371/journal.pone.0064281
  6. Biomolecular markers in assessment and treatment of asthma vol.19, pp.4, 2011, https://doi.org/10.1111/resp.12284
  7. Bifidobacterium breve and Lactobacillus rhamnosus treatment is as effective as budesonide at reducing inflammation in a murine model for chronic asthma vol.15, pp.1, 2011, https://doi.org/10.1186/1465-9921-15-46
  8. FIZZ1 promotes airway remodeling through the PI3K/Akt signaling pathway in asthma vol.7, pp.5, 2011, https://doi.org/10.3892/etm.2014.1580
  9. Fibroblast-myofibroblast transition is differentially regulated by bronchial epithelial cells from asthmatic children vol.16, pp.None, 2011, https://doi.org/10.1186/s12931-015-0185-7
  10. Diosmetin prevents TGF-β1-induced epithelial-mesenchymal transition via ROS/MAPK signaling pathways vol.153, pp.None, 2011, https://doi.org/10.1016/j.lfs.2016.04.023
  11. Dietary flavanones and citrus fruits influence cytokines and thyroid transcription factor-1 in an HDM-induced chronic asthma murine model vol.26, pp.None, 2011, https://doi.org/10.1016/j.jff.2016.08.033
  12. Bacillus Calmette-Guerin alleviates airway inflammation and remodeling by preventing TGF-β1 induced epithelial–mesenchymal transition vol.13, pp.8, 2011, https://doi.org/10.1080/21645515.2017.1313366
  13. MicroRNA-145 down-regulates mucin 5AC to alleviate airway remodeling and targets EGFR to inhibit cytokine expression vol.8, pp.28, 2011, https://doi.org/10.18632/oncotarget.17933
  14. The Toxicological Mechanisms of Environmental Soot (Black Carbon) and Carbon Black: Focus on Oxidative Stress and Inflammatory Pathways vol.8, pp.None, 2011, https://doi.org/10.3389/fimmu.2017.00763
  15. New targets for resolution of airway remodeling in obstructive lung diseases vol.7, pp.None, 2018, https://doi.org/10.12688/f1000research.14581.1
  16. Epigallocatechin-3-gallate inhibits inflammation and epithelial-mesenchymal transition through the PI3K/AKT pathway via upregulation of PTEN in asthma vol.41, pp.2, 2018, https://doi.org/10.3892/ijmm.2017.3292
  17. Type 2-High Severe Asthma with and without Bronchiectasis: A Prospective Observational Multicentre Study vol.14, pp.None, 2021, https://doi.org/10.2147/jaa.s332245
  18. Bixin protects mice against bronchial asthma though modulating PI3K/Akt pathway vol.101, pp.no.pb, 2011, https://doi.org/10.1016/j.intimp.2021.108266