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Published ahead of print on February 1, 2005, doi:10.1164/rccm.200409-1249OC
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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 1096-1102, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200409-1249OC

Original Article

Protective Effects of Tiotropium Bromide in the Progression of Airway Smooth Muscle Remodeling

Reinoud Gosens, I. Sophie T. Bos, Johan Zaagsma and Herman Meurs

Department of Molecular Pharmacology, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands

Correspondence and requests for reprints should be addressed to Reinoud Gosens, Ph.D., Department of Molecular Pharmacology, University Centre for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. E-mail: r.gosens{at}rug.nl

Rationale: Recent findings have demonstrated that muscarinic M3 receptor stimulation enhances airway smooth muscle proliferation to peptide growth factors in vitro. Because both peptide growth factor expression and acetylcholine release are known to be augmented in allergic airway inflammation, it is possible that anticholinergics protect against allergen-induced airway smooth muscle remodeling in vivo. Objective: We investigated the effects of treatment with the long-acting muscarinic receptor antagonist tiotropium on airway smooth muscle changes in a guinea pig model of ongoing allergic asthma. Results: Twelve weekly repeated allergen challenges induced an increase in airway smooth muscle mass in the noncartilaginous airways. This increase was not accompanied by alterations in cell size, indicating that the allergen-induced changes were entirely from increased airway smooth muscle cell number. Morphometric analysis showed no allergen-induced changes in airway smooth muscle area in the cartilaginous airways. However, repeated ovalbumin challenge enhanced maximal contraction of open tracheal ring preparations ex vivo. This was associated with an increase in smooth muscle–specific myosin expression in the lung. Treatment with inhaled tiotropium considerably inhibited the increase in airway smooth muscle mass, myosin expression, and contractility. Conclusions: These results indicate a prominent role for acetylcholine in allergen-induced airway smooth muscle remodeling in vivo, a process that has been thus far considered to be primarily caused by growth factors and other mediators of inflammation. Therefore, muscarinic receptor antagonists, like the long-acting anticholinergic tiotropium bromide, could be beneficial in preventing chronic airway hyperresponsiveness and decline in lung function in allergic asthma.

Key Words: acetylcholine • airway remodeling • anticholinergics • asthma • muscarinic receptors




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