Inhibition of matrix metalloproteinase-9 by doxycycline reduces airway inflammation and hyperresponsiveness in a murine model of toluene diisocyanate-induced asthma

Abstract Rationale 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 due, at least in part, to an excess of extracellular matrix deposition in the airway wall. Matrix metalloproteinases (MMPs) are major proteolytic enzymes that are involved in extracellular matrix (ECM) turnover because of their ability to cleave all proteins constituting ECM. Previous studies have reported that MMP-9 might play a role in chronic airway inflammation and remodeling in asthma. Methods We used a BALB/c mouse model for TDI-induced asthma to determine the effect of a MMP-inhibiting antibiotic agent, doxycycline and 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 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. Conclusions These findings suggest that doxycycline may reduce airway inflammation and hyperresponsiveness through phosphatidylinositol 3-kinase pathway in a murine model of TDI-induced asthma.