Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade.

RATIONALE Airway inflammation in asthma is accompanied by structural changes, including goblet cell metaplasia, smooth muscle cell layer thickening, and subepithelial fibrosis. This allergen-induced airway remodeling can be replicated in a mouse asthma model. OBJECTIVES The study goal was to determine whether established airway remodeling in a mouse asthma model is reversible by administration of the cysteinyl leukotriene (CysLT)1 receptor antagonist montelukast, the corticosteroid dexamethasone, or the combination montelukast + dexamethasone. METHODS BALB/c mice, sensitized by intraperitoneal ovalbumin (OVA) as allergen, received intranasal OVA periodically Days 14-73 and montelukast or dexamethasone or placebo from Days 73-163. MEASUREMENTS AND MAIN RESULTS Allergen-induced trafficking of eosinophils into the bronchoalveolar lavage fluid and lung interstitium and airway goblet cell metaplasia, smooth muscle cell layer thickening, and subepithelial fibrosis present on Day 73 persisted at Day 163, 3 mo after the last allergen challenge. Airway hyperreactivity to methacholine observed on Day 73 in OVA-treated mice was absent on Day 163. In OVA-treated mice, airway eosinophil infiltration and goblet cell metaplasia were reduced by either montelukast or dexamethasone alone. Montelukast, but not dexamethasone, reversed the established increase in airway smooth muscle mass and subepithelial collagen deposition. By immunocytochemistry, CysLT1 receptor expression was significantly increased in airway smooth muscle cells in allergen-treated mice compared with saline-treated controls and was reduced by montelukast, but not dexamethasone, administration. CONCLUSIONS These data indicate that established airway smooth muscle cell layer thickening and subepithelial fibrosis, key allergen-induced airway structural changes not modulated by corticosteroids, are reversible by CysLT1 receptor blockade therapy.

[1]  J. Milbrandt,et al.  Early Growth Response Gene 1–mediated Apoptosis Is Essential for Transforming Growth Factor β1–induced Pulmonary Fibrosis , 2004, The Journal of experimental medicine.

[2]  T. Fukuda,et al.  Leukotriene D4 stimulates collagen production from myofibroblasts transformed by TGF-beta. , 2004, The Journal of allergy and clinical immunology.

[3]  E. Chi,et al.  Increase in laminin expression in allergic airway remodelling and decrease by dexamethasone , 2004, European Respiratory Journal.

[4]  M. Inman Is there a place for anti-remodelling drugs in asthma which may not display immediate clinical efficacy? , 2004, European Respiratory Journal.

[5]  E. Eves,et al.  Human bronchial smooth muscle cell lines show a hypertrophic phenotype typical of severe asthma. , 2004, American journal of respiratory and critical care medicine.

[6]  C. Page,et al.  Platelets are necessary for airway wall remodeling in a murine model of chronic allergic inflammation. , 2004, Blood.

[7]  Hiroshi Tanaka,et al.  Increased airway vascularity in newly diagnosed asthma using a high-magnification bronchovideoscope. , 2003, American journal of respiratory and critical care medicine.

[8]  S. Shore Modeling airway remodeling: the winner by a nose? , 2003, American journal of respiratory and critical care medicine.

[9]  M. Mishima,et al.  Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma. , 2003, American journal of respiratory and critical care medicine.

[10]  M. Kojima,et al.  Mouse model of airway remodeling: strain differences. , 2003, American journal of respiratory and critical care medicine.

[11]  Rakesh K. Kumar,et al.  Inhibition of Inflammation and Remodeling by Roflumilast and Dexamethasone in Murine Chronic Asthma , 2003, Journal of Pharmacology and Experimental Therapeutics.

[12]  E. Raz,et al.  Resolution of airway inflammation following ovalbumin inhalation: comparison of ISS DNA and corticosteroids. , 2003, American journal of respiratory cell and molecular biology.

[13]  M. Aubier,et al.  Airway structural alterations selectively associated with severe asthma. , 2003, American journal of respiratory and critical care medicine.

[14]  J. Stankova,et al.  CysLT1 receptor upregulation by TGF-beta and IL-13, but not IL-4, is associated with bronchial smooth muscle cell proliferation in response to LTD4 , 2003 .

[15]  Q. Hamid,et al.  Inhibition of allergic airways inflammation and airway hyperresponsiveness in mice by dexamethasone: role of eosinophils, IL-5, eotaxin, and IL-13. , 2003, The Journal of allergy and clinical immunology.

[16]  D. Dorscheid,et al.  Corticosteroid-induced apoptosis in mouse airway epithelium: effect in normal airways and after allergen-induced airway inflammation. , 2003, The Journal of allergy and clinical immunology.

[17]  A. Trifilieff,et al.  In vivo and in vitro effects of SAR 943, a rapamycin analogue, on airway inflammation and remodeling. , 2003, American journal of respiratory and critical care medicine.

[18]  P. Hellings,et al.  Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma. , 2003, American journal of respiratory cell and molecular biology.

[19]  J. Stankova,et al.  CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4. , 2003, The Journal of allergy and clinical immunology.

[20]  A. Bush,et al.  Early thickening of the reticular basement membrane in children with difficult asthma. , 2003, American journal of respiratory and critical care medicine.

[21]  W. Henderson,et al.  Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. , 2003, The Journal of allergy and clinical immunology.

[22]  H. Inoue,et al.  Differential regulation by glucocorticoid of interleukin-13-induced eosinophilia, hyperresponsiveness, and goblet cell hyperplasia in mouse airways. , 2003, American journal of respiratory and critical care medicine.

[23]  P. O'Byrne,et al.  Dysfunction and remodeling of the mouse airway persist after resolution of acute allergen-induced airway inflammation. , 2002, American journal of respiratory cell and molecular biology.

[24]  M. Kondo,et al.  Interleukin-13 induces goblet cell differentiation in primary cell culture from Guinea pig tracheal epithelium. , 2002, American journal of respiratory cell and molecular biology.

[25]  R. Homer,et al.  Transgenic Overexpression of Interleukin (IL)-10 in the Lung Causes Mucus Metaplasia, Tissue Inflammation, and Airway Remodeling via IL-13-dependent and -independent Pathways* , 2002, The Journal of Biological Chemistry.

[26]  Rakesh K. Kumar,et al.  Modeling allergic asthma in mice: pitfalls and opportunities. , 2002, American journal of respiratory cell and molecular biology.

[27]  Jeffrey D. Morton,et al.  Viral induction of a chronic asthma phenotype and genetic segregation from the acute response. , 2002, The Journal of clinical investigation.

[28]  Philip Smith,et al.  IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. , 2002, Immunity.

[29]  P. O'Byrne,et al.  The effect of cysteinyl leukotrienes on growth of eosinophil progenitors from peripheral blood and bone marrow of atopic subjects. , 2002, The Journal of allergy and clinical immunology.

[30]  L. Fregonese,et al.  Cysteinyl leukotrienes induce human eosinophil locomotion and adhesion molecule expression via a CysLT1 receptor‐mediated mechanism , 2002, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[31]  K. J. Macleod,et al.  High resolution computed tomographic assessment of airway wall thickness in chronic asthma: reproducibility and relationship with lung function and severity , 2002, Thorax.

[32]  E. Chi,et al.  A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. , 2002, American journal of respiratory and critical care medicine.

[33]  Steven Sun,et al.  Apoptosis of airway epithelial cells induced by corticosteroids. , 2001, American journal of respiratory and critical care medicine.

[34]  P. Jeffery Remodeling in asthma and chronic obstructive lung disease. , 2001, American journal of respiratory and critical care medicine.

[35]  R. Pellegrino,et al.  On the functional consequences of bronchial basement membrane thickening. , 2001, Journal of applied physiology.

[36]  R. Pauwels,et al.  Fluticasone inhibits but does not reverse allergen-induced structural airway changes. , 2001, American journal of respiratory and critical care medicine.

[37]  P. Barnes,et al.  Corticosteroids, IgE, and atopy. , 2001, The Journal of clinical investigation.

[38]  C. Austin,et al.  Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. , 2001, American journal of respiratory and critical care medicine.

[39]  C. Bertrand,et al.  Time course of inflammatory and remodeling events in a murine model of asthma: effect of steroid treatment. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[40]  H. Sampson,et al.  The chinese herbal medicine formula MSSM-002 suppresses allergic airway hyperreactivity and modulates TH1/TH2 responses in a murine model of allergic asthma. , 2000, The Journal of allergy and clinical immunology.

[41]  S. Sanjar,et al.  Airway subepithelial fibrosis in a murine model of atopic asthma: suppression by dexamethasone or anti-interleukin-5 antibody. , 2000, American journal of respiratory cell and molecular biology.

[42]  S. Kilfeather,et al.  Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals. , 2000, American journal of respiratory and critical care medicine.

[43]  W. Henderson,et al.  Soluble IL-4 Receptor Inhibits Airway Inflammation Following Allergen Challenge in a Mouse Model of Asthma1 , 2000, The Journal of Immunology.

[44]  Y. Qin,et al.  TRFK-5 reverses established airway eosinophilia but not established hyperresponsiveness in a murine model of chronic asthma. , 1999, American journal of respiratory and critical care medicine.

[45]  D D Donaldson,et al.  Interleukin-13: central mediator of allergic asthma , 1998 .

[46]  D B Corry,et al.  Requirement for IL-13 independently of IL-4 in experimental asthma. , 1998, Science.

[47]  J. Beesley,et al.  Induction, duration, and resolution of airway goblet cell hyperplasia in a murine model of atopic asthma: effect of concurrent infection with respiratory syncytial virus and response to dexamethasone. , 1998, American journal of respiratory cell and molecular biology.

[48]  R. Panettieri,et al.  Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction In vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. , 1998, American journal of respiratory cell and molecular biology.

[49]  Y. Nakamura,et al.  Expression of growth factors and remodelling of the airway wall in bronchial asthma. , 1998, Thorax.

[50]  E. Chi,et al.  Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. , 1997, The Journal of clinical investigation.

[51]  E. Gelfand,et al.  Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. , 1997, American journal of respiratory and critical care medicine.

[52]  R. Flavell,et al.  A novel role for murine IL-4 in vivo: induction of MUC5AC gene expression and mucin hypersecretion. , 1997, American journal of respiratory cell and molecular biology.

[53]  D Olivieri,et al.  Airways remodeling is a distinctive feature of asthma and is related to severity of disease. , 1997, Chest.

[54]  E. Chi,et al.  The importance of leukotrienes in airway inflammation in a mouse model of asthma , 1996, The Journal of experimental medicine.

[55]  A. Foresi,et al.  Bronchial responsiveness to distilled water and methacholine and its relationship to inflammation and remodeling of the airways in asthma. , 1996, American journal of respiratory and critical care medicine.

[56]  L. Boulet,et al.  Airway responsiveness and bronchial-wall thickness in asthma with or without fixed airflow obstruction. , 1995, American journal of respiratory and critical care medicine.

[57]  D. Woodward,et al.  Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro , 1994, Journal of leukocyte biology.

[58]  M. Ebina,et al.  Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. , 1993, The American review of respiratory disease.

[59]  T. Haahtela,et al.  Leukotriene E4 and granulocytic infiltration into asthmatic airways , 1993, The Lancet.

[60]  S. Kunkel,et al.  Binding of leukotriene C4 to rat lung fibroblasts and stimulation of collagen synthesis in vitro. , 1988, Biochemistry.

[61]  S. Kunkel,et al.  Regulation of Macrophage‐Derived Fibroblast Growth Factor Release by Arachidonate Metabolites , 1987, Journal of leukocyte biology.