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Remodeling and Airway Hyperresponsiveness but Not Cellular Inflammation Persist after Allergen Challenge in Asthma

¹ Allergy and Clinical Immunology Section, ² Leukocyte Biology Section, and ³ Medical Research Council and Asthma U.K. Centre in Allergic Mechanisms of Asthma, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, South Kensington, London, United Kingdom

Correspondence and requests for reprints should be addressed to A. Barry Kay, Emeritus Professor of Allergy and Clinical Immunology, Leukocyte Biology Section, Sir Alexander Fleming Building, Imperial College London, London, SW7 2AZ, UK. E-mail: a.b.kay{at}imperial.ac.uk

Rationale: Airway hyperresponsiveness (AHR) increases up to 2 weeks after allergen inhalational challenge of subjects with asthma who show a late-phase asthmatic reaction (dual responders). Cellular inflammation and airway remodeling are increased 24 hours after allergen challenge.

Objectives: To determine whether persistence of increased AHR is associated with persistent activation of remodeling and enhanced inflammation.

Methods: Fiberoptic bronchoscopy was performed at baseline and at 24 hours and 7 days after allergen inhalational challenge of dual responders with mild–moderate asthma. At each time point, AHR, spirometry, and expression of tenascin (extracellular matrix protein), procollagen I, procollagen III, and heat shock protein (HSP)-47 (markers of collagen synthesis), and -smooth muscle actin (myofibroblasts) were evaluated as markers of activation of airway remodeling, together with numbers of mucosal major basic protein–positive eosinophils, CD68⁺ macrophages, CD3⁺, CD4⁺, CD8⁺ T cells, elastase-positive neutrophils, and tryptase-positive mast cells.

Measurements and Main Results: AHR was increased from baseline at 24 hours and 7 days after allergen challenge. Reticular basement membrane tenascin expression was elevated at 24 hours and returned to baseline levels at 7 days. Reticular basement membrane procollagen III expression was significantly elevated at 7 days. Expression of procollagen I, HSP-47, and -smooth muscle actin were all higher at 7 days compared with 24 hours. At 24 hours, eosinophil, macrophage, neutrophil, and CD3⁺ T cells were increased but had returned to baseline by 7 days.

Conclusions: In dual responders with asthma, the 24-hour increase in airway wall cellular inflammation after allergen challenge resolves by 7 days, whereas the increases in AHR and markers of remodeling persist.

Key Words: asthma • airway hyperresponsiveness • inflammation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The relationship of airway hyperresponsiveness (AHR) to the activation and resolution of inflammatory and remodeling events in asthma remains undefined. It is suggested that AHR can be dissociated from cellular inflammation but not remodeling. What This Study Adds to the Field Increases in AHR after allergen challenge remain associated with remodeling but not cellular inflammation. Persistence of AHR is not dependent on sustained inflammatory cell recruitment.

 

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