ISO-1, a Macrophage Migration Inhibitory Factor Antagonist, Inhibits Airway Remodeling in a Murine Model of Chronic Asthma

Airway remodeling is the process of airway structural change that occurs in patients with asthma in response to persistent inflammation and leads to increasing disease severity. Drugs that decrease this persistent inflammation play a crucial role in managing asthma episodes. Mice sensitized (by intraperitoneal administration) and then challenged (by inhalation) with ovalbumin (OVA) develop an extensive eosinophilic inflammatory response, goblet cell hyperplasia, collagen deposition, airway smooth muscle thickening, and airway wall area increase, similar to pathologies observed in human asthma. We used OVA-sensitized/challenged mice as a murine model of chronic allergic airway inflammation with subepithelial fibrosis (i.e., asthma). In this OVA mouse model, mRNA and protein of macrophage migration inhibitory factor (MIF) are upregulated, a response similar to what has been observed in the pathogenesis of acute inflammation in human asthma. We hypothesized that MIF induces transforming growth factor-β1 (TGF-β1) synthesis, which has been shown to play an important role in asthma and airway remodeling. To explore the role of MIF in the development of airway remodeling, we evaluated the effects of an MIF small-molecule antagonist, (S,R)3-(4-hy-droxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), on pathologies associated with the airway-remodeling process in the OVA mouse model. We found that administration of ISO-1 significantly mitigated all symptoms caused by OVA treatment. In addition, the treatment of OVA-sensitized mice with the MIF antagonist ISO-1 significantly reduced TGF-β1 mRNA levels in pulmonary tissue and its protein level in bronchial alveolar lavage fluid supernatants. We believe the repression of MIF in the ISO-1 treatment group led to the significant suppression observed in the inflammatory responses associated with the allergen-induced lung inflammation and fibrosis in our murine asthma (OVA) model. Our results implicate a possible function of MIF in the pathogenesis of chronic asthma and suggest that MIF might be an important therapeutic target for airway remodeling.

[1]  J. Viola,et al.  Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation , 2007, European journal of immunology.

[2]  I. Miki,et al.  Blockade of macrophage migration inhibitory factor (MIF) prevents the antigen-induced response in a murine model of allergic airway inflammation , 2007, Inflammation Research.

[3]  R. Irwin,et al.  Side effects with inhaled corticosteroids: the physician's perception. , 2006, Chest.

[4]  Y. Nasuhara,et al.  Role of macrophage migration inhibitory factor in ovalbumin-induced airway inflammation in rats , 2006, European Respiratory Journal.

[5]  A. Koch,et al.  Migration inhibitory factor up-regulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 via Src, PI3 kinase, and NFkappaB. , 2006, Blood.

[6]  I. Adcock,et al.  Update on glucocorticoid action and resistance. , 2006, The Journal of allergy and clinical immunology.

[7]  N. Khalil,et al.  TGF-β1 increases proliferation of airway smooth muscle cells by phosphorylation of map kinases , 2006, Respiratory research.

[8]  Michael Bacher,et al.  ISO-1 Binding to the Tautomerase Active Site of MIF Inhibits Its Pro-inflammatory Activity and Increases Survival in Severe Sepsis* , 2005, Journal of Biological Chemistry.

[9]  L. Leng,et al.  Role for macrophage migration inhibitory factor in asthma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[10]  D. Ray,et al.  Glucocorticoids suppress macrophage migration inhibitory factor (MIF) expression in a cell-type-specific manner. , 2004, Journal of molecular endocrinology.

[11]  D. Annane,et al.  Corticoids normalize leukocyte production of macrophage migration inhibitory factor in septic shock. , 2005, The Journal of infectious diseases.

[12]  S. Orkin,et al.  A Critical Role for Eosinophils in Allergic Airways Remodeling , 2004, Science.

[13]  M. Lam,et al.  Anti-macrophage migration inhibitory factor reduces transforming growth factor-beta 1 expression in experimental IgA nephropathy. , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[14]  A. Musani,et al.  Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)‐β1, TGF‐β2, interleukin (IL)‐4 and IL‐13 after segmental allergen challenge and their effects on α‐smooth muscle actin and collagen III synthesis by primary human lung fibroblasts , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[15]  D. Broide,et al.  Inhibition of airway remodeling in IL-5-deficient mice. , 2004, The Journal of clinical investigation.

[16]  S. Phipps,et al.  Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. , 2003, The Journal of clinical investigation.

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

[18]  I. Hussain,et al.  CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. , 2002, The Journal of allergy and clinical immunology.

[19]  Stephen C Lazarus,et al.  Banks CORTICOSTEROIDS FOR PERSISTENT ASTHMA SIGNIFICANT VARIABILITY IN RESPONSE TO INHALED Services , 2022 .

[20]  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.

[21]  R. Bucala,et al.  Macrophage migration inhibitory factor is an important mediator in the pathogenesis of gastric inflammation in rats. , 2001, Gastroenterology.

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

[23]  L. Boulet,et al.  Airway hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed versus long-standing mild asthma. Influence of inhaled corticosteroids. , 2000, American journal of respiratory and critical care medicine.

[24]  S. Holgate,et al.  Epithelial damage and response. , 2000, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[25]  E. Silverman,et al.  Heterogeneity of therapeutic responses in asthma. , 2000, British medical bulletin.

[26]  R. Homer,et al.  Airway remodeling in asthma. , 1999, The Journal of clinical investigation.

[27]  W. Busse,et al.  Airway remodeling and repair. , 1999, American journal of respiratory and critical care medicine.

[28]  Tina Peng,et al.  Sustained Mitogen-activated Protein Kinase (MAPK) and Cytoplasmic Phospholipase A2 Activation by Macrophage Migration Inhibitory Factor (MIF) , 1999, The Journal of Biological Chemistry.

[29]  S. Holgate,et al.  Growth factors secreted by bronchial epithelial cells control myofibroblast proliferation: an in vitro co-culture model of airway remodeling in asthma. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[30]  P. Barnes,et al.  Anti-inflammatory actions of glucocorticoids: molecular mechanisms. , 1998, Clinical science.

[31]  S. Szefler,et al.  Difficult-to-control asthma: clinical characteristics of steroid-insensitive asthma. , 1998, The Journal of allergy and clinical immunology.

[32]  R. Martin,et al.  Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. , 1997, American journal of respiratory cell and molecular biology.

[33]  L. Boulet,et al.  Bronchial subepithelial fibrosis correlates with airway responsiveness to methacholine. , 1997, Chest.

[34]  R. Atkins,et al.  The Pathogenic Role of Macrophage Migration Inhibitory Factor in Immunologically Induced Kidney Disease in the Rat , 1997, The Journal of experimental medicine.

[35]  M. Jordana,et al.  Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation. , 1996, American journal of respiratory cell and molecular biology.

[36]  J. Martin,et al.  Methacholine-induced bronchoconstriction and airway smooth muscle in the guinea pig. , 1996, Journal of applied physiology.

[37]  J. Bernhagen,et al.  MIF as a glucocorticoid-induced modulator of cytokine production , 1995, Nature.

[38]  J. Hogg,et al.  Proposed nomenclature for quantifying subdivisions of the bronchial wall. , 1994, Journal of applied physiology.

[39]  P. Paré,et al.  A model of airway narrowing in asthma and in chronic obstructive pulmonary disease. , 1992, The American review of respiratory disease.

[40]  M. Ebina,et al.  Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. , 1992, Chest.

[41]  A. Wanner.  The role of mucus in chronic obstructive pulmonary disease. , 1990, Chest.

[42]  S. Holgate,et al.  SUBEPITHELIAL FIBROSIS IN THE BRONCHI OF ASTHMATICS , 1989, The Lancet.

[43]  A. Cats,et al.  HL-A 27 AND ANKYLOSING SPONDYLITIS , 1975, The Lancet.

[44]  L. Wide,et al.  Clinical significance of specific IgE to common allergens , 1971, Clinical allergy.