Effect of tiotropium bromide on airway inflammation and remodelling in a mouse model of asthma

BACKGROUND: Tiotropium bromide, a long acting muscarinic receptor inhibitor, is a potent agent for patients with bronchial asthma as well as chronic obstructive pulmonary disease. OBJECTIVE: The aim of this study was to evaluate whether tiotropium bromide can inhibit allergen-induced acute and chronic airway inflammation, T helper (Th)2 cytokine production, and airway remodelling in a murine model of asthma. METHODS: Balb/c mice were sensitized and challenged acutely or chronically to ovalbumin (OVA). The impact of tiotropium bromide was assessed using these mice models by histologic, morphometric, and molecular techniques. Moreover, the effect of tiotropium bromide on Th2 cytokine production from purified human peripheral blood mononuclear cells (PBMCs) was assessed. RESULTS: Treatment with tiotropium bromide significantly reduced airway inflammation and the Th2 cytokine production in bronchoalveolar lavage fluid (BALF) in both acute and chronic models of asthma. The levels of TGF-beta1 were also reduced by tiotropium bromide in BALF in a chronic model. The goblet cell metaplasia, thickness of airway smooth muscle, and airway fibrosis were all significantly decreased in tiotropium bromide-treated mice. Moreover, airway hyperresponsiveness (AHR) to serotonin was significantly abrogated by tiotropium bromide in a chronic model. Th2 cytokine production from spleen cells isolated from OVA-sensitized mice was also significantly inhibited by tiotropium bromide and 4-diphenylacetoxy-N-methylpiperidine methiodide, which is a selective antagonist to the M3 receptor. Finally, treatment with tiotropium bromide inhibited the Th2 cytokine production from PBMCs. CONCLUSION: These results indicate that tiotropium bromide can inhibit Th2 cytokine production and airway inflammation, and thus may reduce airway remodelling and AHR in a murine model of asthma.