A Mouse Model for Evaluating the Contribution of Fibrocytes and Myofibroblasts to Airway Remodeling in Allergic Asthma

  • Matthias Schmidt
  • Sabrina Mattoli
Part of the Methods in Molecular Biology book series (MIMB, volume 1032)


Airway remodeling is a term used to collectively indicate bronchial structural changes that may lead to irreversible airflow obstruction and progressive decline in lung function in asthmatic patients. Bronchial myofibroblasts contribute to airway remodeling by producing collagenous proteins in the subepithelial zone and by increasing the density of contractile cells in the bronchial wall. A substantial proportion of bronchial myofibroblasts in asthma differentiate from circulating mesenchymal progenitor cells known as fibrocytes. Here, we describe a mouse model of allergic asthma for evaluating the functional role of fibrocytes and myofibroblasts in this disease and the inhibitory effects of novel therapeutic candidates.

Key words

Airway remodeling Asthma Fibrocytes Mice Myofibroblasts 


  1. 1.
    National Asthma Education Prevention Program (2007) Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma – summary report 2007. J Allergy Clin Immunol 120(5 Suppl):S94–S138Google Scholar
  2. 2.
    Pascual RM, Peters SP (2009) The irreversible component of persistent asthma. J Allergy Clin Immunol 124:883–890PubMedCrossRefGoogle Scholar
  3. 3.
    Durrani SR, Viswanathan RK, Busse WW (2011) What effect does asthma treatment have on airway remodeling? Current perspectives. J Allergy Clin Immunol 128:439–448PubMedCrossRefGoogle Scholar
  4. 4.
    Jeffery PK (2004) Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 1:176–183PubMedCrossRefGoogle Scholar
  5. 5.
    Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, Chu HW (1999) Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 160:1001–1008PubMedCrossRefGoogle Scholar
  6. 6.
    Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV (1995) T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 180:388–395CrossRefGoogle Scholar
  7. 7.
    Roberts CR (1995) Is asthma a fibrotic disease? Chest 107:111S–117SPubMedCrossRefGoogle Scholar
  8. 8.
    Chu HW, Halliday JL, Martin RJ, Leung DY, Szefler SJ, Wenzel SE (1998) Collagen deposition in large airways may not differentiate severe asthma from milder forms of the disease. Am J Respir Crit Care Med 158:1936–1944PubMedCrossRefGoogle Scholar
  9. 9.
    Wilson JW, Li X (1997) The measurement of reticular basement membrane and submucosal collagen in the asthmatic airway. Clin Exp Allergy 27:363–371CrossRefGoogle Scholar
  10. 10.
    Huang J, Olivenstein R, Taha R, Hamid Q, Ludwig M (1999) Enhanced proteoglycan deposition in the airway wall of atopic asthmatics. Am J Respir Crit Care Med 160:725–729PubMedCrossRefGoogle Scholar
  11. 11.
    Pini L, Hamid Q, Shannon J, Lemelin L, Olivenstein R, Ernst P, Lemièr C, Martin JG, Ludwig MS (2007) Differences in proteoglycans deposition in the airways of moderate and severe asthmatics. Eur Respir J 29:71–77PubMedCrossRefGoogle Scholar
  12. 12.
    Brewster CE, Howarth PH, Djukanovic R, Wilson J, Hogate ST, Roche WR (1990) Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 3:507–511PubMedCrossRefGoogle Scholar
  13. 13.
    Gabbrielli S, Di Lollo S, Stanflin N, Romagnoli P (1994) Myofibroblasts and elastic and collagen fiber hyperplasia in the bronchial mucosa: a possible basis for the progressive irreversibility of airflow obstruction in asthma. Pathologica 86:157–160PubMedGoogle Scholar
  14. 14.
    Gizycki MJ, Adelroth E, Rogers AV, O’Byrne PM, Jeffery PK (1997) Myofibroblast involvement in the allergen-induced late response in mild atopic asthma. Am J Respir Cell Mol Biol 16:664–673PubMedCrossRefGoogle Scholar
  15. 15.
    Kariyawasam HH, Aizen M, Barkans J, Robinson DS, Kay AB (2007) Remodeling and airway hyperesponsiveness but not cellular inflammation persist after allergen challenge in asthma. Am J Respir Crit Care Med 175:896–904PubMedCrossRefGoogle Scholar
  16. 16.
    Kelly MM, O’Connor TM, Leigh R, Otis J, Gwozd C, Gauvreau GM, Gauldie J, O’Byrne PM (2010) Effects of budesonide and formoterol on allergen-induced airway responses, inflammation, and airway remodeling in asthma. J Allergy Clin Immunol 125:349–356.e13PubMedCrossRefGoogle Scholar
  17. 17.
    Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S (2003) Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 171:380–389PubMedGoogle Scholar
  18. 18.
    Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A (1994) Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1:71–81PubMedGoogle Scholar
  19. 19.
    Chesney J, Metz C, Stavitsky AB, Baker M, Bucala R (1998) Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 160:419–425PubMedGoogle Scholar
  20. 20.
    Abe R, Donnelly SC, Peng T, Bucala R, Metz CN (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 166:7556–7562PubMedGoogle Scholar
  21. 21.
    Bianchetti L, Barczyk M, Cardoso J, Schmidt M, Bellini A, Mattoli S (2012) Extracellular matrix remodelling properties of fibrocytes. J Cell Mol Med 16:483–495PubMedCrossRefGoogle Scholar
  22. 22.
    Bellini A, Marini MA, Bianchetti L, Barczyk M, Schmidt M, Mattoli S (2012) Interleukin (IL)-4, IL-13, and IL-17A differentially affect the profibrotic and proinflammatory functions of fibrocytes from asthmatic patients. Mucosal Immunol 5:140–149PubMedCrossRefGoogle Scholar
  23. 23.
    Bianchetti L, Marini MA, Isgrò M, Bellini A, Schmidt M, Mattoli S (2012) IL-33 promotes the migration and proliferation of circulating fibrocytes from allergen-exacerbated asthma. Biochem Biophys Res Commun 426:116–121PubMedCrossRefGoogle Scholar
  24. 24.
    Saunders R, Siddiqui S, Kaur D, Doe C, Sutcliffe A, Hollins F, Bradding P, Wardlaw A, Brightling CE (2009) Fibrocyte localization to the airway smooth muscle is a feature of asthma. J Allergy Clin Immunol 123:376–384PubMedCrossRefGoogle Scholar
  25. 25.
    Wang CH, Huang CD, Lin HC, Lee KY, Lin SM, Liu CY, Huang KH, Ko YS, Chung KF, Kuo HP (2008) Increased circulating fibrocytes in asthma with chronic airflow obstruction. Am J Respir Crit Care Med 178:583–591PubMedCrossRefGoogle Scholar
  26. 26.
    Nihlberg K, Larsen K, Hultgårdh-Nilsson A, Malmström A, Bjermer L, Westergren-Thorsson G (2006) Tissue fibrocytes in patients with mild asthma: a possible link to thickness of reticular basement membrane? Respir Res 7:50PubMedCrossRefGoogle Scholar
  27. 27.
    Oh MH, Oh SY, Yu J, Myers AC, Leonard WJ, Liu YJ, Zhu Z, Zheng T (2011) IL-13 induces skin fibrosis in atopic dermatitis by thymic stromal lymphopoietin. J Immunol 186:7232–7242PubMedCrossRefGoogle Scholar
  28. 28.
    Isgrò M, Bianchetti L, Marini MA, Bellini A, Schmidt M, Mattoli S (2012) The C-C motif chemokine ligands CCL5, CCL11 and CCL24 induce the migration of circulating fibrocytes from patients with severe asthma. Mucosal Immunol. doi: 10.1038/mi.2012.109 PubMedGoogle Scholar
  29. 29.
    Miller M, Cho JY, McElwain K, McElwain S, Shim JY, Manni M, Baek JS, Broide DH (2006) Corticosteroids prevent myofibroblast accumulation and airway remodeling in mice. Am J Physiol Lung Cell Mol Physiol 290:L162–L169PubMedCrossRefGoogle Scholar
  30. 30.
    Wegmann M, Göggel R, Sel S, Sel S, Erb KJ, Kalkbrenner G, Renz H, Garn H (2007) Effects of low-molecular-weight CCR-3 antagonist on chronic experimental asthma. Am J Respir Cell Mol Biol 36:61–67PubMedCrossRefGoogle Scholar
  31. 31.
    Locke NR, Royce SG, Wainewright JS, Samuel CS, Tang ML (2007) Comparison of airway remodeling in acute, subacute, and chronic models of allergic airway disease. Am J Respir Cell Mol Biol 36:625–632PubMedCrossRefGoogle Scholar
  32. 32.
    Di Valentin E, Crahay C, Garbacki N, Hennui B, Guéders M, Noël A, Foidart JM, Grooten J, Colige A, Piette J, Cataldo D (2009) New asthma biomarkers: lessons from murine models of acute and chronic asthma. Am J Physiol Lung Cell Mol Physiol 296:L185–L197PubMedCrossRefGoogle Scholar
  33. 33.
    Olmez D, Babayigit A, Erbil G, Karaman O, Bagriyanik A, Yilmaz O, Uzener N (2009) Histopathologic changes in two mouse models of asthma. J Investig Allergol Clin Immunol 19:132–138PubMedGoogle Scholar
  34. 34.
    Murphy PM, Baggiolini M, Charo IF, Herbert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA (2000) International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev 52:145–176PubMedGoogle Scholar
  35. 35.
    Herz U, Braun A, Rückert R, Renz H (1998) Various immunological phenotypes are associated with increased airway responsiveness. Clin Exp Allergy 28:625–634PubMedCrossRefGoogle Scholar
  36. 36.
    Brewer JP, Kisselgof AB, Martin TR (1999) Genetic variability in pulmonary physiological, cellular, and antibody responses to antigen in mice. Am J Respir Crit Care Med 160:1150–1156PubMedCrossRefGoogle Scholar
  37. 37.
    Boyce JA, Austen KF (2005) No audible wheezing: nuggets and conundrums for mouse asthma models. J Exp Med 201:1869–1873PubMedCrossRefGoogle Scholar
  38. 38.
    Kumar RK, Herbert C, Kasper M (2004) Reversibility of airway inflammation and remodelling following cessation of antigen challenge in a model of chronic asthma. Clin Exp Allergy 34:1796–1802PubMedCrossRefGoogle Scholar
  39. 39.
    Raabe OG, Al-Bayati MA, Teague SV, Raslot A (1988) Regional deposition of inhaled monodisperse coarse and fine aerosol particles in small laboratory animals. Ann Occup Hyg 32:53–63CrossRefGoogle Scholar
  40. 40.
    Menache M, Miller F, Raabe O (1995) Particle inhalability curves for humans and small laboratory animals. Ann Occup Hyg 39:317–328PubMedGoogle Scholar
  41. 41.
    Thomas RJ, Webber D, Sellors W, Collinge A, Frost A, Stagg AJ, Bailey SC, Jayasekera PN, Taylor RR, Eley S, Titball RW (2008) Characterization and deposition of respirable large- and small-particle bioaerosols. Appl Environ Microbiol 74:6437–6443PubMedCrossRefGoogle Scholar
  42. 42.
    Hogan SP, Mould A, Kikutani H, Ramsay AJ, Foster SP (1997) Aeroallergen-induced eosinophilic inflammation, lung damage, and airway heperreactivity in mice can occur independently of IL-4 and allergen-specific immunoglobulins. J Clin Invest 99:1329–1339PubMedCrossRefGoogle Scholar
  43. 43.
    Kennedy JD, Hatfield CA, Fidler SF, Winterrowd GE, Haas JV, Chin JE, Richards IM (1995) Phenotypic characterization of T lymphocytes emigrating into lung tissue and the airway lumen after antigen inhalation in sensitized mice. Am J Respir Cell Mol Biol 12:613–623PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Matthias Schmidt
    • 1
  • Sabrina Mattoli
    • 1
  1. 1.Avail Biomedical Research InstituteBaselSwitzerland

Personalised recommendations