Increased thickness of the airway smooth muscle (ASM) layer is a characteristic feature of airway remodelling in both asthma and chronic obstructive pulmonary disease (COPD) [1, 2]. The composition of the ASM layer has been well studied in asthma where the increased thickness of the ASM layer is due to hypertrophy and/or hyperplasia [3–5] of ASM cells. These changes are associated with a concomitant increase in absolute volumes of both ASM and extracellular matrix (ECM), without changes in their relative volume fractions [5]. Although ASM cell hypertrophy has been reported in the large airways of patients with COPD [6], these findings did not exclude the effect of an increase in the volume fraction of ECM on the estimated average volume of the ASM cells [7]. Remodelling of the layer of airway smooth muscle in COPD is characterised by an increase in the extracellular matrix http://ow.ly/YZqhz

Background: Protective effects of deep inspiration (DI) fail in chronic obstructive pulmonary disease (COPD). It is unknown if this reflects abnormal properties of the airway wall. Aim: To determine if the response of the airway wall to stretch is abnormal in COPD. Methods: Subjects undergoing lung surgery (65±3y) had lung function assessed before surgery and a bronchial segment was dissected from resected lung tissue for in vitro study. Subjects with COPD had a post-bronchodilator FEV1/FVC ratio and FEV1 below lower limit of normal. Response to DI was assessed from maximal and partial (M/P) flow ratio. In bronchial segments, bronchodilation to simulated DI was measured from the change in airway volume after a transient stretch. Wall dimensions were measured on fixed airways. Results: The M/P ratio positively correlated with FEV1/FVC (%predicted, p=0.002, r=0.72) and was reduced from 0.87±0.14 (mean±SE) in the control group (n=9) to 0.50±0.08 in the COPD group (n=7, P=0.047). An M/P ratio of <1 indicated that the dominant effect of DI was bronchoconstriction, and the lower ratio in the COPD group reflected greater constriction. Bronchodilation (%volume) to DI in vitro positively correlated with M/P ratio in vivo (p=0.03, r=0.53). However the magnitude of bronchodilation to DI was not different between groups (p=0.42). Airway wall thickness was not related to M/P ratio (p=0.61) or bronchodilation (p=0.96) and was not different between groups (p=0.81). Conclusion: A DI produces bronchoconstriction in subjects not undergoing bronchial challenge, which is greater in subjects with COPD. While the intrinsic response of the airway wall to stretch contributes to the respiratory effect of DI, it is not different in subjects with COPD.

Background and objectiveWhile chronic inflammation of the airway wall and the failure of deep inspiration (DI) to produce bronchodilation are both common to asthma, whether pro-inflammatory cytokines modulate the airway smooth muscle response to strain during DI is unknown. The primary aim of the study was to determine how an inflammatory environment (simulated by the use of pro-inflammatory cytokines) alters the bronchodilatory response to DI.MethodsWe used whole porcine bronchial segments in vitro that were cultured in medium containing tumour necrosis factor and interleukin-1 for 2days. A custom-built servo-controlled syringe pump and pressure transducer was used to measure airway narrowing and to simulate tidal breathing with intermittent DI manoeuvres.ResultsCulture with tumour necrosis factor and interleukin-1 increased airway narrowing to acetylcholine but did not affect the bronchodilatory response to DI.ConclusionThe failure of DI to produce bronchodilation in patients with asthma may not necessarily involve a direct effect of pro-inflammatory cytokines on airway tissue. A relationship between inflammation and airway hyper-responsiveness is supported, however, regulated by separate disease processes than those which attenuate or abolish the bronchodilatory response to DI in patients with asthma.It is unclear whether the attenuated bronchodilatory response to deep inspiration in asthma is related to an inflammatory environment. Using whole bronchial segments in vitro, we show that culture with pro-inflammatory cytokines, tumour necrosis factor and interleukin-1, increases airway narrowing but does not affect the bronchodilatory response to deep inspiration.

PerspectivesCommentaries on Viewpoint: Airway smooth muscle and airway hyperresponsiveness in human asthma: Have we chased the wrong horse?Peter B. Noble, Peter K. McFawn, Howard W. Mitchell, and Thomas K. AnsellPeter B. NobleSchool of Anatomy, Physiology and Human Biology The University of Western Australia, Peter K. McFawnSchool of Anatomy, Physiology and Human Biology The University of Western Australia, Howard W. MitchellSchool of Anatomy, Physiology and Human Biology The University of Western Australia, and Thomas K. AnsellSchool of Anatomy, Physiology and Human Biology The University of Western AustraliaPublished Online:15 Apr 2014https://doi.org/10.1152/japplphysiol.00025.2014MoreSectionsPDF (39 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat PAUSE FOR DEEP INSPIRATIONto the editor: The Viewpoint by Professor Lutchen is timely and appropriate (3). There is now uncertainty as to the importance of airway smooth muscle (ASM) dynamics to normal airway function and whether disruption in the airway-lung dynamic environment contributes to airway hyperresponsiveness (AHR). Seemingly negative findings in airways in vitro, in which simulated tidal breathing failed to provide dominant control of airway responsiveness (1, 2, 4, 5), have led to the trepidation so clearly expressed by Lutchen in assigning too much importance to this dynamic mechanism. Although Lutchen proposes that the “chasm between a tiny piece of excised ASM tissue and a breathing lung inside a human is enormous” we are not sure bronchial tubes do not leave a large gap unbridged. Although bronchial tubes are our own preferred model, can we be sure the “real breathing” matches what happens during a bronchial challenge? How large are the transmural pressures and how much does the ASM stretch if respiratory effort is increased to overcome the added impedance? We also do not share the fear that the literature concentrates too much on ASM dynamics. There is enough information on airway inflammation and innervation in airway disease to fill textbooks many times over, yet no compelling mechanism surfaced to explain AHR. Much could be gained by revisiting early work under more physiologically relevant dynamic conditions. The field has not simply backed one horse. Present and past strategies are to make several wagers, at a greater outlay, but increasing the probability of a win.REFERENCES1. LaPrad AS, Szabo TL, Suki B, Lutchen KR. Tidal stretches do not modulate responsiveness of intact airways in vitro. J Appl Physiol 109: 295–304, 2010.Link | ISI | Google Scholar2. Lavoie TL, Krishnan R, Siegel HR, Maston ED, Fredberg JJ, Solway J, Dowell ML. Dilatation of the constricted human airway by tidal expansion of lung parenchyma. Am J Respir Crit Care Med 186: 225–232, 2012.Crossref | PubMed | ISI | Google Scholar3. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we chased the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google Scholar4. Noble PB, Jones RL, Cairncross A, Elliot JG, Mitchell HW, James AL, McFawn PK. Airway narrowing and bronchodilation to deep inspiration in bronchial segments from subjects with and without reported asthma. J Appl Physiol 114: 1460–1471, 2013.Link | ISI | Google Scholar5. Noble PB, Jones RL, Needi ET, Cairncross A, Mitchell HW, James AL, McFawn PK. Responsiveness of the human airway in vitro during deep inspiration and tidal oscillation. J Appl Physiol 110: 1510–1518, 2011.Link | ISI | Google ScholarREFERENCES1. LaPrad AS, Szabo TL, Suki B, Lutchen KR. Tidal stretches do not modulate responsiveness of intact airways in vitro. J Appl Physiol 109: 295–304, 2010.Link | ISI | Google Scholar2. Lavoie TL, Krishnan R, Siegel HR, Maston ED, Fredberg JJ, Solway J, Dowell ML. Dilatation of the constricted human airway by tidal expansion of lung parenchyma. Am J Respir Crit Care Med 186: 225–232, 2012.Crossref | PubMed | ISI | Google Scholar3. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we chased the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google Scholar4. Noble PB, Jones RL, Cairncross A, Elliot JG, Mitchell HW, James AL, McFawn PK. Airway narrowing and bronchodilation to deep inspiration in bronchial segments from subjects with and without reported asthma. J Appl Physiol 114: 1460–1471, 2013.Link | ISI | Google Scholar5. Noble PB, Jones RL, Needi ET, Cairncross A, Mitchell HW, James AL, McFawn PK. Responsiveness of the human airway in vitro during deep inspiration and tidal oscillation. J Appl Physiol 110: 1510–1518, 2011.Link | ISI | Google ScholarCAN'T DECIDE WHETHER TO CHASE YOUR FAVORITE HORSE? GROOM IT FIRST WITH OCCAM'S RAZORJason H. T. Bates.Author AffiliationsProfessor University of Vermont College of Medicine.to the editor: Explaining the airway hyperresponsiveness of asthma has sustained an industry of competing theories for decades, largely due to the plethora of disparate mechanistic possibilities (1). Any claim of preeminence for a particular theory in this complex field should thus raise eyebrows. Lutchen takes aim here (2) at the hypothesis that asthma is all about stretching the airway smooth muscle (ASM). This notion has taken hold in recent years due to numerous studies at the cell and tissue strip levels revealing complex dynamic behavior that invokes various molecular intracacies within the contractile machinery of ASM (2). Perhaps not surprisingly, the functional significance of these intracacies has been eagerly extrapolated up to the scale of the whole lung in vivo. But biology can be infuriatingly contrary; just because a particular phenomenon makes its presence strongly felt at one level of length scale, this does not mean that its signature will necessarily manifest in some obvious way at other (higher) levels of scale. Why this happens is a fascinating question in its own right, but one thing is certain—predicting biological behavior at one length scale from that at another is fraught with the danger that you might end up chasing the wrong horse. Identifying the right horse begins in the experimental lab at the pertinent length scale, with the subsequent grooming of theory proceeding under the watchful eye of Occam and Einstein to make sure it is as simple as possible (but no simpler).REFERENCES1. Berend N, Salome CM, King GG. Mechanisms of airway hyperresponsiveness in asthma. Respirology 13: 624–631, 2008.Crossref | PubMed | ISI | Google Scholar2. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we backed the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google ScholarREFERENCES1. Berend N, Salome CM, King GG. Mechanisms of airway hyperresponsiveness in asthma. Respirology 13: 624–631, 2008.Crossref | PubMed | ISI | Google Scholar2. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we backed the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google ScholarHOLD YOUR HORSESChun Y. Seow.Author AffiliationsProfessor University of British Columbia.to the editor: The quick action of beta2-agonist in bronchodilation may have given us a wrong impression about the intimacy between airway smooth muscle (ASM) behavior and the function of a living breathing lung. As correctly pointed out by Lutchen (4), many factors other than ASM dysfunction could contribute to the impaired lung function seen in asthma. The cautionary reminder by Lutchen came as a result of some recent findings suggesting that tidal breathing and deep inspirations (DIs) may not impose sufficiently large strains on ASM to reduce its contractility, and therefore DI-induced bronchodilation may have nothing to do with ASM (1, 3). However, before we eliminate ASM as a player in the DI-induced bronchodilation there are at least two issues that need to be addressed. Firstly, we need to know the exact transpulmonary pressure in a contractile-agonist-challenged lung. There is evidence that parenchyma stiffens when activated by acetylcholine (2). For the same (volume wise) DIs taken with and without bronchochallenge the transmural pressure of airways will be greater in the former, and this needs to be taken into consideration in experiments using airway segments. Secondly, we need to know the degree of ASM activation during bronchochallenges. It is unlikely that ASM cells are maximally activated during a bronchochallenge, especially when epithelial layer of the airways is intact. At submaximal activation, DIs will elicit greater ASM strains. The question is then, with an appropriate oscillation-amplitude of transmural pressure applied to an airway segment, which is submaximally activated, will we see any ASM effect?REFERENCES1. Ansell TK, McFawn PK, Mitchell HW, Noble PB. Bronchodilatory response to deep inspiration in bronchial segments: the effects of stress vs. strain J Appl Physiol 115: 505–513, 2013.Link | ISI | Google Scholar2. Dolhnikoff M, Morin J, Ludwig MS. Human lung parenchyma responds to contractile stimulation. Am J Respir Crit Care Med 158: 1607–1612, 1998.Crossref | ISI | Google Scholar3. Harvey BC, Parameswaran H, Lutchen KR. Can tidal breathing with deep inspirations of intact airways create sustained bronchoprotection or bronchodilation? J Appl Physiol 115: 436–445, 2013.Link | ISI | Google Scholar4. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we backed the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google ScholarREFERENCES1. Ansell TK, McFawn PK, Mitchell HW, Noble PB. Bronchodilatory response to deep inspiration in bronchial segments: the effects of stress vs. strain J Appl Physiol 115: 505–513, 2013.Link | ISI | Google Scholar2. Dolhnikoff M, Morin J, Ludwig MS. Human lung parenchyma responds to contractile stimulation. Am J Respir Crit Care Med 158: 1607–1612, 1998.Crossref | ISI | Google Scholar3. Harvey BC, Parameswaran H, Lutchen KR. Can tidal breathing with deep inspirations of intact airways create sustained bronchoprotection or bronchodilation? J Appl Physiol 115: 436–445, 2013.Link | ISI | Google Scholar4. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we backed the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google ScholarWE BETTER RIDE THE LIVE HORSEVito Brusasco and .Author AffiliationsProfessor of Respiratory Medicine.Riccardo Pellegrino.Author AffiliationsUniversity of Genoa, Italy.to the editor: In his Viewpoint, Dr. Lutchen (4) challenges the concept that a depressed bronchodilator response to a deep inspiration (DI) in asthma is related to the inability of airway smooth muscle (ASM) to lengthen with the increase in lung volume. His arguments are mainly based on in vitro data that appear to be inconsistent with the effects of tidal stretching and DI in vivo. We agree that additional mechanisms regulating airway caliber may confound the effect of stress and strain on ASM. Nevertheless, there are data showing consistent effects of strain in isolated ASM and DI in vivo. Examples are the similar potency of stretching and isoproterenol in relaxing ASM in vitro (2) and similar bronchodilator effects of exercise hyperpnea and maximal doses of albuterol in vivo (4). Also consistent data in vitro and in vivo are that strain rather than stress is the main mechanism underlying the effects of DI on ASM tone (3) and airway caliber (1). Although some effects of strain or DI are not dissimilar between healthy subjects and subjects with asthma, important differences have been reported that are difficult to explain overlooking the role of ASM. For example, reducing strain completely abolished the bronchodilator effect of DI in subjects with asthma but only partially in healthy subjects (1). In conclusion, we concur with Dr. Lutchen that airway narrowing and its reversal by DI is a complex phenomenon, possibly involving several mechanisms. Yet we do not believe that there is currently enough evidence to dismiss the key role of ASM in asthma.REFERENCES1. Gobbi A, Pellegrino RG, Gulotta C, Antonelli A, Pompilio PP, Crimi C, Torchio R, Dutto L, Parola P, Dellaca RL, Brusasco V. Short-term variability of respiratory impedance and effect of deep breath in asthmatic and healthy subjects with airway smooth muscle activation and unloading. J Appl Physiol 115: 708–715, 2013.Link | ISI | Google Scholar2. Gump A, Haughney L, Fredberg J. Relaxation of activated airway smooth muscle: relative potency of isoproterenol vs. tidal stretch. J Appl Physiol 90: 2306–2310, 2001.Link | ISI | Google Scholar3. Harvey BC, Parameswaran H, Lutchen KR. Can tidal breathing with deep inspirations of intact airways create sustained bronchoprotection or bronchodilation? J Appl Physiol 115: 436–445, 2013.Link | ISI | Google Scholar4. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we backed the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google Scholar5. Milanese M, Saporiti R, Bartolini S, Pellegrino R, Baroffio M, Brusasco V, Crimi E. Bronchodilator effects of exercise hyperpnea and albuterol in mild-to-moderate asthma. J Appl Physiol 107: 494–499, 2009.Link | ISI | Google ScholarREFERENCES1. Gobbi A, Pellegrino RG, Gulotta C, Antonelli A, Pompilio PP, Crimi C, Torchio R, Dutto L, Parola P, Dellaca RL, Brusasco V. Short-term variability of respiratory impedance and effect of deep breath in asthmatic and healthy subjects with airway smooth muscle activation and unloading. J Appl Physiol 115: 708–715, 2013.Link | ISI | Google Scholar2. Gump A, Haughney L, Fredberg J. Relaxation of activated airway smooth muscle: relative potency of isoproterenol vs. tidal stretch. J Appl Physiol 90: 2306–2310, 2001.Link | ISI | Google Scholar3. Harvey BC, Parameswaran H, Lutchen KR. Can tidal breathing with deep inspirations of intact airways create sustained bronchoprotection or bronchodilation? J Appl Physiol 115: 436–445, 2013.Link | ISI | Google Scholar4. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we backed the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google Scholar5. Milanese M, Saporiti R, Bartolini S, Pellegrino R, Baroffio M, Brusasco V, Crimi E. Bronchodilator effects of exercise hyperpnea and albuterol in mild-to-moderate asthma. J Appl Physiol 107: 494–499, 2009.Link | ISI | Google ScholarRESPONSE TO VIEWPOINT: “AIRWAY SMOOTH MUSCLE AND AIRWAY HYPERRESPONSIVENESS IN HUMAN ASTHMA: HAVE WE CHASED THE WRONG HORSE?”Gwen Skloot, Alkis Togias, and Nicola Scichilone.Author AffiliationsMount Sinai Hospital New York, New York.to the editor: We agree with Ken Lutchen that “riding only” one “horse” is not an optimal approach to researching a highly complex problem (1). But we have yet to see compelling evidence that periodic lengthening of ASM does not influence contractile function. Working at the in vivo level, we are struck by the finding that a 10-wk rowing exercise program of sedentary, healthy individuals reduces airway responsiveness to methacholine by 50%, in the absence of deep inspirations, with no appreciable changes in baseline lung function (2). In the opposite direction, we see evidence of AHR and impaired DI effects in individuals with obesity who have no asthma (5). We are limited by not knowing what level of ASM lengthening rowing exercise achieves, what level of reduction in lengthening obesity induces, and whether repetitiveness/duration of lengthening is more important than magnitude in achieving contractile changes. We also do not know the potential role of atelectasis, as pointed out by Lutchen. Yet we believe that the lengthening hypothesis is not “out” and that utilizing “nonasthma” conditions, as in our early study (4), is a useful strategy for future research.In vivo pharmacologic manipulations can also offer significant insights. Dr. Lutchen asks about the role of inflammation. When we used high-dose inhaled corticosteroids in people with mild asthma, it was after removal of inflammation that a strong correlation between methacholine PC20 and DI-induced bronchoprotection was revealed, indicating that the steroid-resistant component of AHR is where DI and airway stretch may be most relevant (3).REFERENCES1. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we backed the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google Scholar2. Scichilone N, Morici G, Zangla D, Chimenti L, Davi E, Reitano S, Paterno A, Santagata R, Togias A, Bellia V, Bonsignore MR. Effects of exercise training on airway responsiveness and airway cells in healthy subjects. J Appl Physiol 109: 288–294, 2010.Link | ISI | Google Scholar3. Scichilone N, Permutt S, Bellia V, Togias A. Inhaled corticosteroids and the beneficial effect of deep inspiration in asthma. Am J Respir Crit Care Med 172: 693–699, 2005.Crossref | ISI | Google Scholar4. Skloot G, Permutt S, Togias A. Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration. J Clin Invest 96: 2393–2403, 1995.Crossref | PubMed | ISI | Google Scholar5. Skloot G, Schechter C, Desai A, Togias A. Impaired response to deep inspiration in obesity. J Appl Physiol 111: 726–734, 2011.Link | ISI | Google ScholarREFERENCES1. Lutchen KR. Viewpoint: Airway smooth muscle stretch and airway hyperresponsiveness in asthma: Have we backed the wrong horse? J Appl Physiol; doi:10.1152/japplphysiol.00968.2013.Link | ISI | Google Scholar2. Scichilone N, Morici G, Zangla D, Chimenti L, Davi E, Reitano S, Paterno A, Santagata R, Togias A, Bellia V, Bonsignore MR. Effects of exercise training on airway responsiveness and airway cells in healthy subjects. J Appl Physiol 109: 288–294, 2010.Link | ISI | Google Scholar3. Scichilone N, Permutt S, Bellia V, Togias A. Inhaled corticosteroids and the beneficial effect of deep inspiration in asthma. Am J Respir Crit Care Med 172: 693–699, 2005.Crossref | ISI | Google Scholar4. Skloot G, Permutt S, Togias A. Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration. J Clin Invest 96: 2393–2403, 1995.Crossref | PubMed | ISI | Google Scholar5. Skloot G, Schechter C, Desai A, Togias A. Impaired response to deep inspiration in obesity. J Appl Physiol 111: 726–734, 2011.Link | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByAirway diameter at different transpulmonary pressures in ex vivo sheep lungs: implications for deep inspiration-induced bronchodilation and bronchoprotectionShou-Jin Dong, Lu Wang, Pasquale Chitano, Harvey O. Coxson, Peter D. Paré, and Chun Y. Seow20 September 2021 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 321, No. 4Bronchodilatory effect of deep inspiration in freshly isolated sheep lungsWilliam D. Wong*, Lu Wang*, Peter D. Paré, and Chun Y. Seow1 February 2017 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 312, No. 2Overexpression of soluble ADAM33 promotes a hypercontractile phenotype of the airway smooth muscle cell in ratExperimental Cell Research, Vol. 349, No. 1A one-horse race can have only one winnerKenneth R. Lutchen15 April 2014 | Journal of Applied Physiology, Vol. 116, No. 8 More from this issue > Volume 116Issue 8April 2014Pages 1116-1118 Copyright & PermissionsCopyright © 2014 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00025.2014PubMed24736833History Published online 15 April 2014 Published in print 15 April 2014 Metrics

Background and Purpose In asthmatic patients, airflow limitation is at least partly reversed by administration of pharmacological bronchodilators, typically β 2 ‐adrenoceptor agonists. In addition to receptor‐mediated bronchodilation, the dynamic mechanical environment of the lung itself can reverse bronchoconstriction. We have now explored the possibility that bronchodilators exert a synergistic effect with oscillatory loads by virtue of reducing airway wall stiffness, and therefore, enhancing the bronchodilatory response to breathing manoeuvres. Experimental Approach Whole porcine bronchial segments in vitro were contracted to carbachol and relaxed to the non‐specific β‐adrenoceptor agonist, isoprenaline, under static conditions or during simulated breathing manoeuvres. Key Results The bronchodilatory response to isoprenaline was greater during breathing manoeuvres compared with the response under static conditions. As the bronchodilatory response to breathing manoeuvres is dependent upon airway smooth muscle ( ASM ) strain, and therefore, airway wall stiffness, our findings are likely to be explained by the effect of isoprenaline on reducing airway wall stiffness, which increased ASM strain, producing greater bronchodilation. Conclusions and Implications A contribution of reduced airway stiffness and increased ASM strain to the bronchodilator action of isoprenaline is shown, suggesting that oscillatory loads act synergistically with pharmacologically mediated bronchodilation. The implications for the treatment of asthma are that reducing airway wall stiffness represents a potential target for novel pharmacological agents.

In isolated airway smooth muscle (ASM) strips, an increase or decrease in ASM length away from its current optimum length causes an immediate reduction in force production followed by a gradual time-dependent recovery in force, a phenomenon termed length adaptation. In situ, length adaptation may be initiated by a change in transmural pressure (Ptm), which is a primary physiological determinant of ASM length. The present study sought to determine the effect of sustained changes in Ptm and therefore, ASM perimeter, on airway function. We measured contractile responses in whole porcine bronchial segments in vitro before and after a sustained inflation from a baseline Ptm of 5 cmH2O to 25 cmH2O, or deflation to -5 cmH2O, for ∼50 min in each case. In one group of airways, lumen narrowing and stiffening in response to electrical field stimulation (EFS) were assessed from volume and pressure signals using a servo-controlled syringe pump with pressure feedback. In a second group of airways, lumen narrowing and the perimeter of the ASM in situ were determined by anatomical optical coherence tomography. In a third group of airways, active tension was determined under isovolumic conditions. Both inflation and deflation reduced the contractile response to EFS. Sustained Ptm change resulted in a further decrease in contractile response, which returned to baseline levels upon return to the baseline Ptm. These findings reaffirm the importance of Ptm in regulating airway narrowing. However, they do not support a role for ASM length adaptation in situ under physiological levels of ASM lengthening and shortening.

The present study presents preliminary findings on how structural/functional abnormalities of the airway wall relate to excessive airway narrowing and reduced bronchodilatory response to deep inspiration (DI) in subjects with a history of asthma. Bronchial segments were acquired from subjects undergoing surgery, mostly to remove pulmonary neoplasms. Subjects reported prior doctor-diagnosed asthma (n = 5) or had no history of asthma (n = 8). In vitro airway narrowing in response to acetylcholine was assessed to determine maximal bronchoconstriction and sensitivity, under static conditions and during simulated tidal and DI maneuvers. Fixed airway segments were sectioned for measurement of airway wall dimensions, particularly the airway smooth muscle (ASM) layer. Airways from subjects with a history of asthma had increased ASM (P = 0.014), greater maximal airway narrowing under static conditions (P = 0.003), but no change in sensitivity. Maximal airway narrowing was positively correlated with the area of the ASM layer (r = 0.58, P = 0.039). In tidally oscillating airways, DI produced bronchodilation in airways from the control group (P = 0.0001) and the group with a history of asthma (P = 0.001). While bronchodilation to DI was reduced with increased airway narrowing (P = 0.02; r = -0.64)), when the level of airway narrowing was matched, there was no difference in magnitude of bronchodilation to DI between groups. Results suggest that greater ASM mass in asthma contributes to exaggerated airway narrowing in vivo. In comparison, the airway wall in asthma may have a normal response to mechanical stretch during DI. We propose that increased maximal airway narrowing and the reduced bronchodilatory response to DI in asthma are independent.