Effect of Bronchoconstriction on Airway Remodeling in Asthma
Christopher L. Grainge, Ph.D., Laurie C.K. Lau, Ph.D., Jonathon A. Ward, B.Sc., Valdeep Dulay, B.Sc., Gemma Lahiff, B.Sc., Susan Wilson, Ph.D., Stephen Holgate, D.M., Donna E. Davies, Ph.D., and Peter H. Howarth, D.M.
Asthma is a common chronic respiratory condition characterized clinically by an excessive tendency toward reversible airway narrowing. This may arise in response to everyday environmental exposure and is worsened both by intercurrent infection and, in sensitized persons, by allergen exposure. In pathological terms, asthma is characterized by airway inflammation and by structural changes in airway tissues, such as epithelial goblet-cell hyperplasia, subepithelial collagen deposition, and smooth-muscle hypertrophy — collectively referred to as airway remodeling.1-3 Since an inhaled-allergen challenge in atopic asthma induces eosinophilic inflammation of the airway and changes in the extracellular matrix,4 and since a reduction in airway eosinophils has been reported to reduce certain markers of airway remodeling,5 such structural changes in the tissues have been considered a consequence of eosinophilic airway inflammation.6 This paradigm, however, fails to account for the potential contribution of airway narrowing to airway remodeling. Bronchoconstriction generates excessive mechanical forces within the airways that distort tissue cells,7,8 and mechanical forces within other organs are known to induce tissue remodeling.9-11 In vitro studies in a variety of models have shown that ex vivo compression of the airway epithelium results in changes that mimic those identified and associated with remodeling in vivo.12-15 We therefore hypothesized that the airway narrowing induced by allergen exposure in vivo in patients with asthma may in itself be a sufficient stimulus for the development of airway remodeling and that such remodeling is not solely dependent on induced recruitment of airway eosinophils.
To test this hypothesis, we performed repeated challenges with exposure to either allergen (to induce bronchoconstriction with airway eosinophil recruitment) or methacholine (to induce bronchoconstriction alone) in volunteers who had mild atopic asthma. Two additional groups of volunteers with asthma served as controls, undergoing repeated challenges with either saline placebo (to control for the challenge procedures) or methacholine after they had received albuterol to prevent bronchoconstriction (to control for any additional nonbronchodilator, receptor-mediated actions of methacholine within the airways). The effect of these challenges on the airway was evaluated by assessing changes in markers of airway remodeling in endobronchial tissue obtained by fiberoptic bronchoscopy before and after the challenge.
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