Doxycycline reduces airway inflammation and hyperresponsiveness in a murine model of toluene diisocyanate-induced asthma

BACKGROUND: Toluene diisocyanate (TDI) is a leading cause of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is an inflammatory disease of the airways characterized by airway remodeling caused, at least in part, by an excess of extracellular matrix deposition in the airway wall. Matrix metalloproteinases (MMPs) are major proteolytic enzymes that are involved in extracellular matrix turnover because of their ability to cleave all proteins constituting extracellular matrix. Previous studies have reported that MMP-9 might play a role in chronic airway inflammation and remodeling in asthma. OBJECTIVE: An aim of the current study was to evaluate the effects of MMP-inhibiting antibiotic, doxycycline, and MMP inhibitors on hyperresponsiveness and inflammation of the airways in TDI-induced asthma. METHODS: We used a murine model for TDI-induced asthma to examine the effect of doxycycline or MMP inhibitors on bronchial inflammation and airway hyperresponsiveness. RESULTS: The following typical pathophysiologic features are observed in the lungs of the mice: airway inflammation, airway hyperresponsiveness, and increased expression of MMP-9 mRNA and protein. Administration of doxycycline and MMP inhibitors reduced all of these pathophysiologic findings. In addition, the increased phosphorylated Akt but not Akt protein levels in lung tissues after TDI inhalation were significantly reduced by the administration of doxycycline and MMP inhibitors. CONCLUSION: These findings suggest that doxycycline may reduce airway inflammation and hyperresponsiveness through phosphatidylinositol 3-kinase pathway in a murine model of TDI-induced asthma.