TNF and IL-1β exposure increases airway narrowing but does not alter the bronchodilatory response to deep inspiration in airway segments

Background and objective: While 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. Methods: We used whole porcine bronchial segments in vitro that were cultured in medium containing tumour necrosis factor and interleukin-1β 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. Results: Culture with tumour necrosis factor and interleukin-1β increased airway narrowing to acetylcholine but did not affect the bronchodilatory response to DI. Conclusion: The 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

Airway smooth muscle dynamics and hyperresponsiveness: In and outside the clinic

The primary functional abnormality in asthma is airway hyperresponsiveness (AHR)—excessive airway narrowing to bronchoconstrictor stimuli. Our understanding of the underlying mechanism(s) producing AHR is incomplete. While structure-function relationships have been evoked to explain AHR (e.g., increased airway smooth muscle (ASM) mass in asthma) more recently there has been a focus on how the dynamic mechanical environment of the lung impacts airway responsiveness in health and disease. The effects of breathing movements such as deep inspiration reveal innate protective mechanisms in healthy individuals that are likely mediated by dynamic ASM stretch but which may be impaired in asthmatic patients and thereby facilitate AHR. This perspective considers the evidence for and against a role of dynamic ASM stretch in limiting the capacity of airways to narrow excessively. We propose that lung function measured after bronchial provocation in the laboratory and changes in lung function perceived by the patient in everyday life may be quite different in their dependence on dynamic ASM stretch

Bronchodilatory response to deep inspiration in bronchial segments: The effects of stress vs. strain

Bronchodilatory response to deep inspiration in bronchial segments: the effects of stress vs. strain. J Appl Physiol 115: 505-513, 2013. First published May 30, 2013; doi:10.1152/japplphysiol.01286.2012.-During deep inspirations (DI), a distending force is applied to airway smooth muscle (ASM; i.e., stress) and the muscle is lengthened (i.e., strain), which produces a transient reversal of bronchoconstriction (i.e., bronchodilation). The aim of the present study was to determine whether an increase in ASM stress or the accompanying increase in strain mediates the bronchodilatory response to DI. We used whole porcine bronchial segments in vitro and a servo-controlled syringe pump that applied fixed-transmural pressure (Ptm) or fixed-volume oscillations, simulating tidal breathing and DI. The relationship between ASM stress and strain during oscillation was altered by increasing doses of acetylcholine, which stiffened the airway wall, or by changing the rate of inflation during DI, which utilized the viscous properties of the intact airway. Bronchodilation to DI was positively correlated with ASM strain (range of r values from 0.81 to 0.95) and negatively correlated with stress (range of r values from -0.42 to -0.98). Fast fixed-Ptm DI produced greater bronchodilation than slow DI, despite less ASM strain. Fast fixed-volume DI produced greater bronchodilation than slow DI, despite identical ASM strain. We show that ASM strain, rather than stress, is the critical determinant of bronchodilation and, unexpectedly, that the rate of inflation during DI also impacts on bronchodilation, independent of the magnitudes of either stress or strain

Pharmacological bronchodilation is partially mediated by reduced airway wall stiffness

Background and Purpose In asthmatic patients, airflow limitation is at least partly reversed by administration of pharmacological bronchodilators, typically β2-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

Potent bronchodilation and reduced stiffness by relaxant stimuli under dynamic conditions

Airway relaxation in response to isoprenaline, sodium nitroprusside (SNP) and electrical field stimulation (EFS) was compared under static and dynamic conditions. The capacity of relaxants to reduce airway stiffness and, thus, potentially contribute to bronchodilation was also investigated. Relaxation responses were recorded in fluid filled bronchial segments from pigs under static conditions and during volume oscillations simulating tidal and twice tidal manoeuvres. Bronchodilation was assessed from the reduction in carbachol-induced lumen pressure, at isovolume points in pressure cycles produced by volume oscillation, and stiffness was assessed from cycle amplitudes. Under static conditions, all three inhibitory stimuli produced partial relaxation of the carbacholinduced contraction. Volume oscillation alone also reduced the contraction in an amplitude- dependent manner. However, maximum relaxation was observed when isoprenaline or SNP were combined with volume oscillation, virtually abolishing contraction at the highest drug concentrations. The proportional effects of isoprenaline and EFS were not different under static or oscillating conditions, whereas relaxation to SNP was slightly greater in oscillating airways. All three inhibitory stimuli also strongly reduced carbachol-induced airway stiffening. The current authors conclude that bronchoconstriction is strongly suppressed by combining the inhibitory stimulation of airway smooth muscle with cyclical mechanical strains. The capacity of airway smooth muscle relaxants to also reduce stiffness may further contribute to bronchodilation

Effects of simulated tidal and deep breathing on immature airway contraction to acetylcholine and nerve stimulation

Background and objective: In adults, respiratory movements, such as tidal and deep breaths, reduce airway smooth muscle force and cause bronchodilation. Evidence suggests that these beneficial effects of oscillatory strain do not occur in children, possibly because of reduced coupling of the airways to lung tissue or maturational differences in the intrinsic response of the airways to oscillatory strain. Methods: The bronchodilator effects of oscillatory strain were compared in isolated airway segments from immature (3-4 weeks and 8-10 weeks old) and mature (18-20 weeks old) pigs. The lumen of fluid-filled bronchi was volume-oscillated to simulate tidal breaths and 0.5×, 2× and 4× tidal volumes. Contractions to acetylcholine and electrical field stimulation were recorded from the lumen pressure and were compared under oscillating and static conditions. Airway stiffness was determined from the amplitude of the lumen pressure cycles and the volume of oscillation. Results: Volume oscillation reduced contractions to acetylcholine and electrical field stimulation in an amplitude-dependent manner and the percentage reduction was the same for the different stimuli across all age groups. There was no difference in the relaxed dynamic stiffness of airways from the different age groups. Conclusions: The intrinsic response of the airway wall to equivalent dynamic strain did not differ in airways from pigs of different ages. These findings suggest that mechanisms external to the airway wall may produce age-related differences in the response to lung inflation during development

Does smooth muscle in an intact airway undergo length adaptation during a sustained change in transmural pressure?

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

Distribution of airway narrowing responses across generations and at branching points, assessed in vitro by anatomical optical coherence tomography

Background: Previous histological and imaging studies have shown the presence of variability in the degree of bronchoconstriction of airways sampled at different locations in the lung (i.e., heterogeneity). Heterogeneity can occur at different airway generations and at branching points in the bronchial tree. Whilst heterogeneity has been detected by previous experimental approaches, its spatial relationship either within or between airways is unknown.Methods: In this study, distribution of airway narrowing responses across a portion of the porcine bronchial tree was determined in vitro. The portion comprised contiguous airways spanning bronchial generations (#3-11), including the associated side branches. We used a recent optical imaging technique, anatomical optical coherence tomography, to image the bronchial tree in three dimensions. Bronchoconstriction was produced by carbachol administered to either the adventitial or luminal surface of the airway. Luminal cross sectional area was measured before and at different time points after constriction to carbachol and airway narrowing calculated from the percent decrease in luminal cross sectional area.Results: When administered to the adventitial surface, the degree of airway narrowing was progressively increased from proximal to distal generations (r = 0.80 to 0.98, P < 0.05 to 0.001). This 'serial heterogeneity' was also apparent when carbachol was administered via the lumen, though it was less pronounced. In contrast, airway narrowing was not different at side branches, and was uniform both in the parent and daughter airways.Conclusions: Our findings demonstrate that the bronchial tree expresses intrinsic serial heterogeneity, such that narrowing increases from proximal to distal airways, a relationship that is influenced by the route of drug administration but not by structural variations accompanying branching sites

Airway narrowing assessed by anatomical optical coherence tomography in vitro: Dynamic airway wall morphology and function

Regulation of airway caliber by lung volume or bronchoconstrictor stimulation is dependent on physiological, structural, and mechanical events within the airway wall, including airway smooth muscle (ASM) contraction, deformation of the mucosa and cartilage, and tensioning of elastic matrices linking wall components. Despite close association between events in the airway wall and the resulting airway caliber, these have typically been studied separately: the former primarily using histological approaches, the latter with a range of imaging modalities. We describe a new optical technique, anatomical optical coherence tomography (aOCT), which allows changes at the luminal surface (airway caliber) to be temporally related to corresponding dynamic movements within the airway wall. A fiber-optic aOCT probe was inserted into the lumen of isolated, liquid-filled porcine airways. It was used to image the response to ASM contraction induced by neural stimulation and to airway inflation and deflation. Comparisons with histology indicated that aOCT provided highresolution images of the airway lumen including mucosal folds, the entire inner wall (mucosa and ASM), and partially the cartilaginous outer wall. Airway responses assessed by aOCT revealed several phenomena in "live" airways (i.e., not fixed) previously identified by histological investigations of fixed tissue, including a geometric relationship between ASM shortening and luminal narrowing, and sliding and bending of cartilage plates. It also provided direct evidence for distensibility of the epithelial membrane and anisotropic behavior of the airway wall. Findings suggest that aOCT can be used to relate changes in airway caliber to dynamic events in the wall of airways