Airway Remodeling in Asthma: Is Bronchospasm the Culprit?
Airway Remodeling in Asthma: Is Bronchospasm the Culprit?
Grainge CL, Lau LC, Ward JA, et al
N Engl J Med. 2011;364:2006-2015
When asthma is severe and long term, it becomes less amenable to treatment -- or less "reversible." This process, remodeling of the airways with peribronchial fibrosis, has been widely attributed to persistent eosinophilic inflammation even though it cannot consistently be prevented by the use of an appropriate anti-inflammatory agent such as an inhaled corticosteroid. Remodeling is manifested by a long-term decline in forced expiratory volume (FEV1) and a reduction in the reversibility of airways obstruction. However, its mechanism has not been established, and its prevention is, therefore, a major unmet need in the long-term course of asthma. A recent study by Grainge and colleagues from the United Kingdom asked whether remodeling could be the result of persistent bronchoconstriction rather than persistent inflammation.
Patients with allergic asthma were given 1 of 4 treatments. One group received a series of inhalations of their allergens, which resulted in bronchoconstriction and eosinophilic inflammation. A second group received inhalations of methacholine, an agent that causes bronchoconstriction without inflammation. A third group (a control group) received methacholine together with albuterol, producing neither bronchoconstriction nor inflammation. A fourth group (also a control group) received only saline inhalations. Remodeling was assessed by histologic and biochemical features of inflammation and repair in airway mucosal biopsies taken 8 days after the last challenge.
The investigators found that methacholine inhalations produced the same amount of bronchoconstriction and airway remodeling as the allergen challenge. However, participants who received methacholine plus albuterol had neither bronchoconstriction nor remodeling. The investigators concluded that it was the bronchoconstriction that produced the remodeling rather than the inflammation.
The conclusion that bronchoconstriction, rather than inflammation, is a mediator -- perhaps the mediator -- of airway remodeling is intriguing if not revolutionary. First, how strong is the evidence provided by this study? A different methodology might have firmed up the outcome, for example, a group who received allergen plus albuterol (or another bronchodilator) to determine whether inflammation in the absence of bronchoconstriction resulted in any remodeling. It would also be interesting to see what effect an inhaled steroid might have in this model, or whether surrogates of airway remodeling could be produced in patients without asthma. Perhaps those studies will follow. This study was relatively brief, lasting just a few days. The basis for evidence of remodeling is surrogate biochemical changes in the airway lining that are several steps removed from airway function and clinical outcomes. Thus, how confidently can the results be extrapolated to a process that occurs over several years in the natural history of the disease? That question remains to be answered. Nevertheless, the findings all point in the direction that bronchoconstriction itself may be sufficient to set the remodeling process in motion, as concluded by Grainge and colleagues.
Although it has been suggested that physical forces can play a role in the maintenance and remodeling of airways in experimental situations, it has not been appreciated that these forces can have important clinical implications. Moreover, the fact that inhaled corticosteroids are so effective in counteracting eosinophilic inflammation, yet do not prevent airway remodeling, has not led clinicians to suspect that bronchoconstriction might be a major contributor. The paradigm may be about to shift. In the clinic, it is necessary to ensure not only that an inhaled corticosteroid is prescribed and taken, but also that bronchospasm is addressed on a maintenance basis. This speaks strongly for the use of a fixed combination of an inhaled corticosteroid plus a long-acting beta2-agonist.
Abstract
Effect of Bronchoconstriction on Airway Remodeling in Asthma
Grainge CL, Lau LC, Ward JA, et al
N Engl J Med. 2011;364:2006-2015
Study Summary
When asthma is severe and long term, it becomes less amenable to treatment -- or less "reversible." This process, remodeling of the airways with peribronchial fibrosis, has been widely attributed to persistent eosinophilic inflammation even though it cannot consistently be prevented by the use of an appropriate anti-inflammatory agent such as an inhaled corticosteroid. Remodeling is manifested by a long-term decline in forced expiratory volume (FEV1) and a reduction in the reversibility of airways obstruction. However, its mechanism has not been established, and its prevention is, therefore, a major unmet need in the long-term course of asthma. A recent study by Grainge and colleagues from the United Kingdom asked whether remodeling could be the result of persistent bronchoconstriction rather than persistent inflammation.
Patients with allergic asthma were given 1 of 4 treatments. One group received a series of inhalations of their allergens, which resulted in bronchoconstriction and eosinophilic inflammation. A second group received inhalations of methacholine, an agent that causes bronchoconstriction without inflammation. A third group (a control group) received methacholine together with albuterol, producing neither bronchoconstriction nor inflammation. A fourth group (also a control group) received only saline inhalations. Remodeling was assessed by histologic and biochemical features of inflammation and repair in airway mucosal biopsies taken 8 days after the last challenge.
The investigators found that methacholine inhalations produced the same amount of bronchoconstriction and airway remodeling as the allergen challenge. However, participants who received methacholine plus albuterol had neither bronchoconstriction nor remodeling. The investigators concluded that it was the bronchoconstriction that produced the remodeling rather than the inflammation.
Viewpoint
The conclusion that bronchoconstriction, rather than inflammation, is a mediator -- perhaps the mediator -- of airway remodeling is intriguing if not revolutionary. First, how strong is the evidence provided by this study? A different methodology might have firmed up the outcome, for example, a group who received allergen plus albuterol (or another bronchodilator) to determine whether inflammation in the absence of bronchoconstriction resulted in any remodeling. It would also be interesting to see what effect an inhaled steroid might have in this model, or whether surrogates of airway remodeling could be produced in patients without asthma. Perhaps those studies will follow. This study was relatively brief, lasting just a few days. The basis for evidence of remodeling is surrogate biochemical changes in the airway lining that are several steps removed from airway function and clinical outcomes. Thus, how confidently can the results be extrapolated to a process that occurs over several years in the natural history of the disease? That question remains to be answered. Nevertheless, the findings all point in the direction that bronchoconstriction itself may be sufficient to set the remodeling process in motion, as concluded by Grainge and colleagues.
Although it has been suggested that physical forces can play a role in the maintenance and remodeling of airways in experimental situations, it has not been appreciated that these forces can have important clinical implications. Moreover, the fact that inhaled corticosteroids are so effective in counteracting eosinophilic inflammation, yet do not prevent airway remodeling, has not led clinicians to suspect that bronchoconstriction might be a major contributor. The paradigm may be about to shift. In the clinic, it is necessary to ensure not only that an inhaled corticosteroid is prescribed and taken, but also that bronchospasm is addressed on a maintenance basis. This speaks strongly for the use of a fixed combination of an inhaled corticosteroid plus a long-acting beta2-agonist.
Abstract
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