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VIEWPOINT
Department of Medicine, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland
You are invited to submit a brief commentary on this Viewpoint, which will be reviewed by Journal editors for possible publication in the Journal of Applied Physiology. Please limit your comment to 250 words and 5 peer-reviewed published references.
THE MAJOR SYMPTOMS of asthma are produced by airway smooth muscle contraction. The role of intrinsic airway structure as a determinant of the magnitude of the contraction is controversial. We evaluated the effect of the smooth muscle contraction in volunteers with moderately severe asthma [forced expiratory volume (FEV)1 = 64% predicted] by virtually eliminating the smooth muscle tension with repeated doses of a 
-agonist, albuterol, until a maximum response in FEV1 occurred and compared the pulmonary function and the high-resolution computed tomography-airways structure on that day with the pulmonary function and structure measured on a previous day under baseline conditions with a steady state of smooth muscle tension (2). We considered the difference in pulmonary function and structure between the 2 days the result of the baseline smooth muscle tension (BSMT). We found that the effect of the muscle contraction on pulmonary function was not related to the magnitude of the contraction, but rather the airway structure that was present in the relaxed airways before the contraction occurred.
The major effect of the BSMT was a nearly 50% increase in the residual volume (RV) and a 15% decrease in FEV1. The major correlate of the baseline FEV1 was the magnitude of the percent change in forced vital capacity (FVC; mean decrease 7%; range –30 to 14%) produced by the BSMT.
The magnitude of the increase in RV was significantly correlated with the ratio of the wall thickness to the diameter of the large airways and the diameter of the medium airways when relaxed with albuterol at total lung capacity (TLC). The dimensions of the small airways had no relationship to the increase in RV. We were surprised that the structural determinants of the increase in RV with BSMT had no effect on the change in FVC. This was because these structural determinants were also correlated with an increase functional residual capacity (FRC) and TLC that nullified the effect of the increase in RV on reducing the FVC. The magnitude of the decrease in the FVC and FEV1 produced by BSMT was correlated with how much the FRC changed relative to RV; i.e., the greater the increase in FRC relative to the increase in RV, the smaller the decrease in FVC. The increase in FRC from the BSMT was highly correlated with the increase in TLC, and we infer that the increase in TLC compensated for the increase in RV and diminished the response of the FVC to the BSMT.
The index we used to quantify how much the FRC increased in relation to the increase in RV [the FRCratio = (FRCBSMT/FRCALB)÷(RVBSMT/RVALB)] was significantly correlated with the response to a methacholine challenge; i.e., the lower the FRCratio, the lower the methacholine log10PC20. Furthermore, the lower the FRCratio, the greater the decrease in FVC and FEV1 from the BSMT. The correlation of the FRCratio with the log10PC20and the magnitude of the change in FEV1 and FVC from the BSMT suggested to us that hyperresponsiveness to a contractile agonist might be more determined by a decreased compensatory change in lung volume than by an increase in the response of the airways smooth muscle itself. Indeed, despite the BSMT causing a significant decrease in the luminal diameter of the three sizes of airways studied, not a single change in pulmonary function produced by the BSMT correlated with the magnitude of the decrease in the diameter.
The FRCratio was correlated with the luminal diameter of the large airways at TLC when the smooth muscle tension was suppressed with albuterol. There was no correlation of the FRCratio with either the small or medium airways, with or without albuterol, or with the wall thickness or ratio of the wall thickness to the luminal diameter of the large airways. The smaller the luminal diameter at TLC of the relaxed large airways, the smaller was FEV1/FVCALB% predicted and the greater was FRCALB%, TLCALB%, and FVCALB%. The magnitude of each of these three lung volumes that was present when the smooth muscle tension was suppressed was significantly correlated with the response to a methacholine challenge; i.e., the greater the lung volume, the smaller the log10PC20. We infer that the increased albuterol lung volumes were the result of dynamic hyperinflation from the increased expiratory resistance arising from the narrowed lumen of the large airways and the decreased FEV1/FVCALB%.
The structure of the relaxed large airways with albuterol played the dominant role in the magnitude of the responsiveness to smooth muscle tension. The ratio of wall thickness to the diameter of the large airways and the diameter of the medium airways were the determinants of the effect of the smooth muscle tension in increasing the RV, presumably through airway closure; but there was no relationship of these determinants to either FEV1/FVCALB% or the magnitude of the albuterol lung volumes. Apparently, the wall thickness of the large airways and the diameter of the medium airways had no significant effect on expiratory resistance; thus no contribution to the magnitude of the dynamic hyperinflation.
It was the diameter of the large airways that determined the magnitude of the dynamic hyperinflation through its effect on FEV1/FVCALB% and expiratory resistance. We formulated a hypothesis (see Fig. 1) that it was the degree of dynamic hyperinflation that was the principal determinant of the magnitude of the FRCratio, and it was the FRCratio that quantified how much reduction in FVC and FEV1 occurred from the increase in RV from smooth muscle tension and how responsive the change in pulmonary function would become to a challenge with a contractile agonist. These findings are summarized in Tables 3 and 4 of Ref. 2.
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In conclusion, dynamic hyperinflation caused by narrowing of large airways is a major determinant of airway hyperresponsiveness in asthma.
FOOTNOTES
Address for reprint requests and other correspondence: S. Permutt, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (e-mail: spermut{at}jhmi.edu)
REFERENCES
This article has been cited by other articles:
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  B. B. Araujo, M. Dolhnikoff, L. F. F. Silva, J. Elliot, J. H. N. Lindeman, D. S. Ferreira, A. Mulder, H. A. P. Gomes, S. M. Fernezlian, A. James, et al. Extracellular matrix components and regulators in the airway smooth muscle in asthma Eur. Respir. J., July 1, 2008; 32(1): 61 - 69. [Abstract] [Full Text] [PDF]
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