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• W2048758931 abstract "INVITED EDITORIALSAirways hyperresponsiveness: a perspective from 15,000 ftCharles G. IrvinCharles G. IrvinVermont Lung Center and Departments of Medicine and Molecular Physiology and Biophysics, University of Vermont, Burlington, VermontPublished Online:01 Apr 2010https://doi.org/10.1152/japplphysiol.00103.2010This is the final version - click for previous versionMoreSectionsPDF (310 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat used as a clinical tool for distinguishing a state of airway “twitchiness” or hyperresponsiveness, bronchial challenge is also utilized to explore the effects of interventions or disease. Bronchial challenge testing has been investigated as a clinical test since Weiss et al. (15), Tiffeneau (12), and Parker et al. (9), whose pioneering work suggested airways hyperresponsiveness was an important feature of asthma. Hargreave and colleagues (4, 7) at McMaster University further developed and validated bronchial challenge test procedures, and for many years it was thought that airways hyperresponsiveness was the sine qua non for asthma. However, subsequent clinical investigations demonstrated that airways hyperresponsiveness was a common feature of many diseases especially those that are often confused with asthma, including cystic fibrosis, bronchitis, and heart disease (1). Hence, today we now know that a state of airways hyperresponsiveness is often sensitive but not specific for having asthma. Nevertheless, airways hyperresponsiveness remains an important feature of asthma especially if it is active or severe. Abnormal airways function is of interest because most diseases of the lung have airway involvement to some degree. It is for these reasons that exploring the mechanisms of airway hyperresponsiveness is scientifically significant. A question we will now turn to is, what causes airways hyperresponsiveness? Rather than introducing the usual facts and hypotheses, I thought for fun that I would put this question to a number of unsuspecting colleagues at several institutions. Their answers were very uniform and I can scientifically report that “common wisdom” holds that airways hyperresponsiveness is entirely due to abnormal function of the airways smooth muscle. This simple, one-factor theory holds that in response to pharmaceutical agonists like methacholine, exercise, and other stimuli, there is a robust and excessive narrowing of the airways due to increased airways smooth muscle shortening. We will now learn that this common wisdom is either wrong or at the least that abnormal airways smooth muscle function is not the complete answer.In a study in the Journal of Applied Physiology, Pellegrino and colleagues (11) sought to investigate the effects on airways responsiveness of taking normal subjects to high-altitude Mount Rosa at 4,559 m (15,000 ft). Their hypothesis was straightforward even if the outcome was not, specifically that a sojourn to 15,000 ft would cause peribronchial edema, which in turn would cause either airways thickening and/or airway parenchymal uncoupling, leading to airways hyperresponsiveness. This hypothesis was a logical extension of the authors previously reported study (10) in which a rapid saline infusion caused airways of normal subjects to become hyperresponsive. So I expect to some surprise the authors found that assent to altitude did not increase airways responsiveness as predicted. Ascent to altitude did cause interstitial lung edema as supported by the observed decreases in static lung compliance, but this finding coupled to a preserved effect of a deep breath suggests that the high-altitude pulmonary edema that did occur did not mechanically uncouple the airways from the parenchyma. Hence mechanical uncoupling was not the reason why airways hyperresponsiveness was not observed. This leaves us with the question, why doesn't the lung exhibit airways hyperresponsiveness at altitude? Here the authors necessarily leave us with deductions and speculations both of which may have important bearing on our understanding of the pathogenesis of lung disease.Let's reconsider several mechanisms that are important determinants of airway function and patency. The first of these is the influence of changing lung volume that can cause marked changes in transmural pressure and thus airway diameter, provided there is a mechanical linkage between the airway wall and the parenchymal tissue attachments. Airway-parenchymal interactions could be involved in the results of this study because altitude sojourn caused the static compliance to decrease. The resultant increase in elastic recoil should increase “tethering” of airways and in turn prevent airway narrowing. Of the factors that influence airway caliber lung volume is a (or even the most) powerful determinate of airway resistance as has been shown in both asthmatic (5,8) and normal subjects (5). Since baseline measures of unchallenged airway caliber didn't change with ascent to altitude, alterations in airway wall thickness would not seem to be involved and in like fashion this finding also eliminates a major role for hypoxia- or hypocapnia-induced bronchospasm. The authors discuss the role of gas density and neural elements but they favor the influence of increased cyclic smooth muscle stretching (6). Under this scenario the increase caused by minute ventilation secondary to effects of altitude acclimatization increases airway stretching and thus would render the airway smooth muscle less responsive to methacholine. The speculation then is that airway responsiveness at altitude is a balance of several opposing mechanisms that determine the ultimate state of responsiveness (Fig. 1).Fig. 1.Schematic represents the real potential for interplay between multiple mechanisms in determining any given state of airways responsiveness. Situation depicted is the effect of high altitude on multiple mechanisms that could potentially determine the ultimate state of airway caliber and responsiveness to an agonist such as methacholine or muscular exercise [see Pellegrino et al. (11)]; however, this balance of mechanisms could apply to other situations (e.g., disease) as well. AHR, airways hyperresponsiveness.Download figureDownload PowerPointWhat the study of Pellegrino et al. (11) underscores is how little we know about the mechanisms of airways responsiveness in vivo in both normal subjects and patients with lung disease. On this point, this study is of interest because it attempted to study in detail the effects of high altitude-induced pulmonary edema. Rather than linking edema to airways hyperresponsivness they uncovered a much more complex situation (Fig. 1). Second, this study demonstrates the power of using more specific physiological end points and how using a suite of end points causes a clearer picture to emerge. In particular it exposes the severe shortcomings of measuring only forced expiratory volume in 1 s (FEV1), because the FEV1 is a polyvalent end point that while robust is unfortunately very nonspecific. We have demonstrated the power of this approach to experimental animals as we have previously shown that in mice airway responsiveness can be caused by changes in airways smooth muscle force (13), epithelium integrity (3), epithelial thickening, and airway closure (14). We would not have been able to make these relatively specific determinations without the use of multiple specific physiological end points. One shortcoming of this approach is that the measurements themselves can alter the outcome, the so-called “phenotyping uncertainty principle” (2). But why should we care what specifically causes airways responsiveness and hyperresponsiveness? We should care because if the principle determinate of airways hyperresponsiveness is airway patency due to fluid or mucus obstruction this is a very different situation from the effects of abnormal smooth muscle function. Specifically, this leads to at least important implications for future research in this area. First, our mechanistic investigations in asthma and other lung diseases must shift from the understanding of how inflammation affects the smooth muscle to how inflammation changes downstream mechanisms such as increased epithelial permeability or mucous hyperplasia and/or liquid accumulation. Second, this understanding clearly opens new avenues of treatment. And for the readers of this Journal, it should underscore the importance of the use of classical measurements of lung function to more thoroughly investigate current theories of lung disease pathogenesis. So classical organ physiology it would seem is not dead and clearly is reaching to new heights.REFERENCES1. ATS Committee on Proficiency Standards. Guidelines for methacholine and exercise challenge testing—1999. Am J Respir Crit Care Med 161: 50–56, 2000.ISI | Google Scholar2. Bates JH , Irvin CG. Measuring lung function in mice: the phenotyping uncertainty principle. J Appl Physiol 94: 1297–1306, 2003.Link | ISI | Google Scholar3. Bates JH , Wagers SS , Norton RJ , Rinaldi LM , Irvin CG. Exaggerated airway narrowing in mice treated with intra-tracheal cationic protein. J Appl Physiol 100: 500–506, 2006.Link | ISI | Google Scholar4. Cockcroft DW , Killian DN , Mellon JJ , Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 7: 235–243, 1977.Crossref | PubMed | Google Scholar5. Ding DJ , Martin JG , Macklem PT. Effects of lung volume on maximal methacholine-induced bronchoconstriction in normal humans. J Appl Physiol 62: 1324–1330, 1987.Link | ISI | Google Scholar6. Fredberg JJ , Inouye DS , Mijailovich SM , Butler JP. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm. Am J Respir Crit Care Med 159: 959–967, 1999.Crossref | PubMed | ISI | Google Scholar7. Hargreave FE , Ryan G , Thomson NC , O'Byrne PM , Latimer K , Juniper EF , Dolovich J. Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clin Immunol 68: 347–355, 1981.Crossref | ISI | Google Scholar8. Irvin CG , Pak J , Martin RJ. Airway-parenchyma uncoupling in nocturnal asthma. Am J Respir Crit Care Med 161: 50–56, 2000.Crossref | ISI | Google Scholar9. Parker CD , Bilbo RE , Reed CE. Methacholine aerosol as test for bronchial asthma. Arch Intern Med 115: 452–458, 1965.Crossref | Google Scholar10. Pellegrino R , Dellaca R , Macklem PT , Aliverti A , Bertini S , Lotti P , Agostoni P , Locatelli A , Brusasco V. Effects of rapid saline infusion on lung mechanics and airway responsiveness in humans. J Appl Physiol 95: 728–734, 2003.Link | ISI | Google Scholar11. Pellegrino R , Pompilio P , Quaranta M , Aliverti A , Kayser B , Miserocchi G , Fasano V , Cogo A , Milanese M , Cornara G , Brusasco V , Dellacà R. Airway responses to methacholine and exercise at high altitude in healthy lowlanders. J Appl Physiol 108: 256–265, 2010.Link | ISI | Google Scholar12. Tiffeneau R. Hypersensibilité cholinergo-histaminique pulmonaire de l'asthmatique. Acta Allergol Suppl (Copenh) 5: 187–221, 1958.Google Scholar13. Wagers SS , Haverkamp HC , Bates JH , Norton RJ , Thompson-Figueroa JA , Sullivan MJ , Irvin CG. Intrinsic and antigen induced airway hyperresponsiveness are the result of divergent physiological mechanisms. J Appl Physiol 102: 221–230, 2007.Link | ISI | Google Scholar14. Wagers SS , Lundblad LKA , Ekman M , Irvin CG , Bates JHT. The allergic mouse model of asthma: normal smooth muscle in an abnormal lung. J Appl Physiol 96: 2019–2027, 2004.Link | ISI | Google Scholar15. Weiss S , Robb GP , Ellis LE. The system effects of histamine in man with special reference to the responses of the cardiovascular system. Arch Intern Med 49: 360–396, 1932. Crossref | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: C. G. Irvin, Dept. of Medicine and Physiology, Univ. of Vermont, Burlington, VT 05405-0075 (e-mail: charles.[email protected]edu). Download PDF Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 108Issue 4April 2010Pages 765-766 Copyright & PermissionsCopyright © 2010 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00103.2010PubMed20133442History Published online 1 April 2010 Published in print 1 April 2010 Metrics" @default.
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