Bronchoconstriction and Airway Remodeling

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Sep 22, 2011 - allergen-induced bronchoconstriction and the sin- gle, short-duration, methacholine-induced bron- choconstriction? Bill B. Brashier, M.B., B.S..


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Bronchoconstriction and Airway Remodeling To the Editor: The article by Grainge and coworkers (May 26 issue)1 suggests that mechanical stress leads to airway remodeling in asthma. If this is the case, why were the remodeling outcomes the same with the dual and prolonged allergen-induced bronchoconstriction and the single, short-duration, methacholine-induced bronchoconstriction? Bill B. Brashier, M.B., B.S. Neha Iyer, M.Sc. Sundeep S. Salvi, M.D., Ph.D. Chest Research Foundation Pune, India [email protected] No potential conflict of interest relevant to this letter was reported. 1. Grainge CL, Lau LCK, Ward JA, et al. Effect of bronchocon-

striction on airway remodeling in asthma. N Engl J Med 2011; 364:2006-15.

To the Editor: Grainge and colleagues found that inhalation of methacholine (an acetylcholine derivative) leads to enhanced epithelial proliferation and mucus production and enhanced subepithelial collagen-band thickness in patients with asthma. These effects were abrogated by pretreatment with albuterol. The authors postulate that the mechanical stimulus of bronchoconstriction explains these findings. We would like to suggest an alternative explanation. Acetylcholine has profound non-neuronal functions in human airways.1 Stimulation of cholinergic receptors on airway epithelial cells leads to enhanced epithelial proliferation and mucus production. In addition, cholinergic agents induce collagen production in fibroblasts and can, therefore, contribute to enhanced collagen-band thickness.1 β2-agonists such as albuterol inhibit the release of acetylcholine from parasympathetic-nerve terminals, thus reducing the amount of endogenous acetylcholine in the airways.2 In addition, albuterol can have direct non-neuronal effects on airway epithelial cells and surrounding structures.3 Thus, the effects of methacholine and albuterol on airway remodeling observed by Grainge and colleagues might in fact result from the direct pharmacologic effects of these drugs. Marek Lommatzsch, M.D.

To the Editor: The findings in the study by Grainge and colleagues contradict the established theory of inflammation as the primary driver of pathological change in asthmatic airways. If bronchoconstriction is the real culprit, then these observations may be applicable to chronic obstructive pulmonary disease (COPD), another condition characterized by airway remodeling. In University of Rostock COPD, tiotropium, a bronchodilator devoid of Rostock, Germany any recognized antiinflammatory properties, has [email protected] been shown to attenuate the postbronchodilator Wolfgang Kummer, M.D. decline in lung function in early disease.1 This Justus-Liebig-University Giessen finding is consistent with a progressive effect of Giessen, Germany bronchodilation in constraining airway remodel- J. Christian Virchow, M.D. ing. Do the authors have any data that address University of Rostock Rostock, Germany this possibility?

No potential conflict of interest relevant to this letter was reported.

Jaymin Morjaria, M.D. Simon Hart, M.D. Alyn H. Morice, M.D.

1. Kummer W, Lips KS, Pfeil U. The epithelial cholinergic sys-

tem of the airways. Histochem Cell Biol 2008;130:219-34.

2. Proskocil BJ, Fryer AD. Beta2-agonist and anticholinergic

University of Hull Cottingham, United Kingdom [email protected] No potential conflict of interest relevant to this letter was reported. 1. Morice AH, Celli B, Kesten S, Lystig T, Tashkin D, Decramer

M. COPD in young patients: a pre-specified analysis of the fouryear trial of tiotropium (UPLIFT). Respir Med 2010;104:1659-67.


drugs in the treatment of lung disease. Proc Am Thorac Soc 2005;2:305-10. 3. Chorley BN, Li Y, Fang S, Park JA, Adler KB. (R)-albuterol elicits antiinflammatory effects in human airway epithelial cells via iNOS. Am J Respir Cell Mol Biol 2006;34:119-27.

To the Editor: The last time I used the term “remodeling” to educate a patient regarding her

n engl j med 365;12  september 22, 2011

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need to keep asthma under good control, she exclaimed “Remodeling? How wonderful! I’d love to have pretty new bronchial tubes!” The article by Grainge et al. and the accompanying editorial1 both perpetuate the use of this imprecise terminology. I implore the respiratory-medicine community to come up with a better way to describe these deleterious structural changes in the airways. Then we can put the paintbrushes and miter saws away for good. Susan R. Bailey, M.D. Fort Worth Allergy and Asthma Associates Fort Worth, TX No potential conflict of interest relevant to this letter was reported. 1. Tschumperlin DJ. Physical forces and airway remodeling in

asthma. N Engl J Med 2011;364:2058-9.

Although COPD, in contrast to asthma, is not associated with exaggerated diurnal variation in lung function, it is possible that tiotropium could have an indirect effect on airway remodeling in this disease. Tiotropium modifies the cough reflex and reduces the frequency of disease exacerbation.3 Cough, which induces airway compression and is a feature both of the disease and of exacerbations, has been linked to airway remodeling.4 We cannot entirely rule out the possibility that the effects of methacholine and the reported protective effects of albuterol are each pharmacologic factors independent of their actions on airway smooth-muscle constriction. Their effect on mechanical airway compression does, however, afford the best explanation. Furthermore, the histopathological effects identified are not consistent with their independent pharmacology, in that beta-agonists do not reverse airway remodeling in asthma5 and cholinergic stimuli stimulate glandular secretion rather than mucus-gland hyperplasia. We appreciate the lack of precision of the term “airway remodeling,” a deficiency that is also evident with airway inflammation and air­ way physiology. Until our language is remodeled, however, there is no term that more precisely defines the structural airway changes in asthma.

The Authors Reply: The basis for the lack of difference in outcomes of airway remodeling with repeated methacholine challenge (single bronchoconstrictor response) and allergen challenge (dual immediate and late bronchoconstrictor responses) is undetermined. One explanation, based on in vitro data,1 is that there is a threshold response, such that once mechanical compression has activated epithelial cells, that additional compression has no further additive effect. An alternative explanation is that the response is Christopher L. Grainge, Ph.D. linked to the rate of change in airway caliber. Peter H. Howarth, D.M. The immediate bronchoconstrictor responses University of Southampton Faculty of Medicine with allergen and methacholine follow a similar Southampton, United Kingdom time course, whereas the late bronchoconstrictor [email protected] response to allergen is considerably slower in onSince publication of their article, the authors report no furset. As such, the airway mechanical compressive ther potential conflict of interest. forces generated during the immediate and late bronchoconstrictor responses are likely to be dif- 1. Park JA, Tschumperlin DJ. Chronic intermittent mechanical stress increases MUC5AC protein expression. Am J Respir Cell ferent. In addition, the different pharmacologic Mol Biol 2009;41:459-66. response to beta-agonists in the early and late 2. Weersink EJ, Aalbers R, Koëter GH, Kauffman HF, De Monresponse, once alteration in airway caliber has chy JG, Postma DS. Partial inhibition of the early and late asthmatic response by a single dose of salmeterol. Am J Respir Crit been taken into account,2 suggests that differ- Care Med 1994;150:1262-7. ent airway mechanisms underlie the immediate 3. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus and late bronchoconstrictor responses to aller- salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093-103. gen. This possibility may also have relevance. 4. Niimi A, Torrego A, Nicholson AG, Cosio BG, Oates TB, Until further experimental data are available, it is Chung KF. Nature of airway inflammation and remodeling in not possible to determine which of these poten- chronic cough. J Allergy Clin Immunol 2005;116:565-70. 5. Roberts JA, Bradding P, Britten KM, et al. The long-acting tial explanations, or indeed others not men- beta2-agonist salmeterol xinafoate: effects on airway inflammationed, accounts for the findings. tion in asthma. Eur Respir J 1999;14:275-82.

n engl j med 365;12  september 22, 2011

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