Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.
"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.
Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may 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."
They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).
Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.
Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.
Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).
Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.
After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.
Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.
"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."
The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."
This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.