title: The tyrosine kinase inhibitor dasatinib reduces lung inflammation and remodelling in experimental allergic asthma.
abstract: OBJECTIVE
  Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in understanding of its pathophysiology, asthma remains a major public health problem, and new therapeutic strategies are urgently needed. In this context, we sought to ascertain whether treatment with the TK inhibitor dasatinib might repair inflammatory and remodelling processes, thus improving lung function, in a murine model of asthma.
  
  
  METHODS
  Animals were sensitized and subsequently challenged, with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, animals were treated with dasatinib, dexamethasone, or saline, every 12 h for 7 consecutive days. Twenty-four hours after the last treatment, the animals were killed, and data were collected. Lung structure and remodelling were evaluated by morphometric analysis, immunohistochemistry, and transmission electron microscopy of lung sections. Inflammation was assessed by cytometric analysis and ELISA, and lung function was evaluated by invasive whole-body plethysmography.
  
  
  RESULTS
  In OVA mice, dasatinib, and dexamethasone led to significant reductions in airway hyperresponsiveness. Dasatinib was also able to attenuate alveolar collapse, contraction index, and collagen fibre deposition, as well as increasing elastic fibre content, in OVA mice. Concerning the inflammatory process, dasatinib reduced inflammatory cell influx to the airway and lung-draining mediastinal lymph nodes, without inducing the thymic atrophy promoted by dexamethasone.
  
  
  CONCLUSIONS
  In this model of allergic asthma, dasatinib effectively blunted the inflammatory and remodelling processes in asthmatic lungs, enhancing airway repair and thus improving lung mechanics.
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: A L
authors.initials: AL
authors.lastname: da Silva
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: R F
authors.initials: RF
authors.lastname: Magalhães
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: V C
authors.initials: VC
authors.lastname: Branco
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: J D
authors.initials: JD
authors.lastname: Silva
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: F F
authors.initials: FF
authors.lastname: Cruz
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: P S
authors.initials: PS
authors.lastname: Marques
authors.affiliation: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: T P T
authors.initials: TP
authors.lastname: Ferreira
authors.affiliation: Laboratory of Cellular and Molecular Physiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: M M
authors.initials: MM
authors.lastname: Morales
authors.affiliation: Laboratory of Inflammation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: Martins
authors.affiliation: Laboratory of Clinical Bacteriology and Immunology, Department of Toxicological and Clinical Analysis, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: P C
authors.initials: PC
authors.lastname: Olsen
authors.affiliation: Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: P R M
authors.initials: PR
authors.lastname: Rocco
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D000069439:Dasatinib / Q000494:pharmacology* / Q000627:therapeutic use; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib