Airway Caliber Research Articles

Role of Nonlinear Serial Elasticity on Airway Smooth Muscle Contraction

Both the elevated shortening velocity and maximal shortening capacity of airway smooth muscle (ASM) in asthmatic airways have been associated with airway hyperresponsiveness, even though the isometric force-generating capacity of the muscle is the same as in normal airways. This paradox may be partly explained by the relaxing role of tidal breathing, which is associated with perturbed equilibria of myosin binding. We have developed a theoretical model of airway narrowing to quantitatively assess how and in what degree the observed alterations in ASM contractility and nonlinear ASM serial elasticity (SE) can account for hyperresponsiveness in asthma. The model includes the elasticity and geometry of the lungs, ASM contractility, and the dynamics of breathing. The airway caliber, proportional to ASM length, is dynamically determined by the balance between the airway wall reaction force (AWRF) and ASM contractile force. AWRF depends on the instantaneous difference between pleural pressure and airway pressure at each generation of Weibel's symmetrical bronchial tree, elasticity and geometry of the airway wall, tethering of the airway to the lung parenchyma, and the state of lung inflation. ASM contractile force depends on myosin binding kinetics and the level of ASM activation. From equliriated ASM length the airway resistance is calculated. The model enables simulation of breathing in normal and asthmatic airways exposed to an increasing dose of spasmogen. Increasing the dose causes a contraction of the ASM, narrowing of the airways, and an exponential increase airway resistance. We show that an airway with asthmatic or sensitized muscle (increased level of myosin LC20 phosphorylation, by 30-50%) narrows faster and significantly more than a normal airway. These results lead to a plausible mechanism by which the rate of bridge cycling and its regulation may account for airway excessive narrowing in asthma.

Pharmacologic bronchodilation response to salbutamol in copd patients

Airway hyperresponsiveness (AHR) is the most characteristic feature of asthma, which is reported in COPD patients and smokers. Increased airway responsiveness to ί-agonists is also demonstrated in asthmatics as well as smokers. However, there is no report regarding AHR to ί-agonist drugs in COPD patients. Therefore, in this study pharmacologic bronchodilation response to salbutamol in COPD patients was examined. The threshold concentrations of inhaled salbutamol required for a 20% change in forced expiratory flow in 1 sec (FEV 1 ) as PC 20 , or a 35% change in specific airway conductance (sGaw) as PC 35 was measured in 14 COPD patients and 14 normal subjects. Airway responsiveness to salbutamol in COPD patients (PC 20 = 14.14 ± 1.62 and PC 35 = 9.70 ± 1.48 mg/l) was significantly lower than normal subjects (PC 20 = 224.57 ± 16.62 and PC 35 = 81.87 ± 8.16 mg/l, P < 0.001 for both cases). The values of FEV 1 and sGaw in COPD patients (56.43 ± 14.45 and 0.081 ± 0.120 respectively) were significantly lower than those of normal subjects (104.07 ± 5.72 and 0.194 ± 0.041 respectively), (P < 0.001 for FEV 1 and P < 0.005 for sGaw). There was a significant correlation between FEV 1 with PC 20 salbutamol (r = 0.862, P < 0.001). The correlations between PC 20 and PC 35 was also statistically significant (r = 0.862, P < 0.001). These results showed increased airway responsiveness of most COPD patients to salbutamol which was highly correlated to airway caliber.

Optimizing maintenance therapy in pediatric asthma

There are different phenotypes of asthma, with phenotype-specific differences in medication response observed. Tobacco smoke exposure reduces corticosteroid responsiveness. Treatment for tobacco smoke-triggered asthma must start with treatment of tobacco dependence. Obesity-associated asthma responds to weight loss and treatment of comorbidities. Immunotherapy and omalizumab are specific therapies for atopic asthma, though its use is limited by expense, inconvenience, need for injections, and toxicities. Leukotriene modifier response is more prominent in viral-triggered asthma. Research on intermittent escalation of controller therapy for asthma shows best results when escalation is substantial and early. Inhaled corticosteroid medications in low-to-moderate doses remain the most important maintenance medication for a broad variety of asthma phenotypes, reducing both impairment and risk. When impairment is not fully controlled by an inhaled corticosteroid, combination with a long-acting beta-agonist, leukotriene modifier, or theophylline can be effective. Inhaled corticosteroid use in children does not appear to influence airway caliber or asthma severity after the medication is stopped. Optimizing maintenance therapy for asthma is not one size fits all. It is important to assess the asthma phenotype in addition to the symptom pattern, in determining optimal maintenance therapy.

Anatomy, pathology, and physiology of the tracheobronchial tree: Emphasis on the distal airways

This article covers the airway tree with respect to anatomy, pathology, and physiology. The anatomic portion discusses various primate groups so as to help investigators understand similarities and differences between animal models. An emphasis is on distal airway findings. The pathology section focuses on the inflammatory responses that occur in proximal and distal airways. The physiologic review brings together the anatomic and pathologic components to the functional state and proposes ways to evaluate the small airways in patients with asthma.

Diffuse idiopathic pulmonary neuroendocrine hyperplasia, chronic eosinophilic pneumonia, and asthma

To the Editors: Herein we report the progression of irreversible airflow obstruction in a patient with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Following an episode of chronic eosinophilic pneumonia associated with raised sputum substance P and infiltration of the interstitum and alveolar spaces with eosinophils, the fixed airflow limitation became variable ( i.e. asthma), requiring treatment with inhaled corticosteroids and long-acting β-agonists. A number of airway diseases, such as smoker's bronchitis, emphysema, asthma, bronchiolitis and bronchiectasis, can lead to chronic airflow limitation 1. However, variability and reversibility of airflow limitation is only observed in asthma. Inflammatory cell infiltration of the airway, particularly with eosinophils, may be one of the mechanisms of variable airflow limitation 2. Although the natural history of eosinophilic bronchitis is not well known, it is believed that it may lead to chronic irreversible airflow limitation 3. However, it is unusual for chronic irreversible airflow limitation to show variability and improvement in airway calibre following treatment with corticosteroids. This case report describes the changes in lung function and response to treatment of a patient with chronic airflow limitation due to smoker's bronchitis and DIPNECH following eosinophilic inflammation of the airway and the interstitium. The case also highlights the importance of measuring airway inflammation in the management of airway diseases. A 65-yr-old female with a history of hypercholesterolemia, vertebral osteoarthritis, gall stone disease and endometriosis but no previous respiratory illness, except a mild intermittent cough for the past 4 yrs, presented with fever, night sweats, worsening cough and weight loss of 6.8 kg (15 lbs). She did not have muscle or joint aches, a skin rash or bowel symptoms. She appeared pale and had inspiratory crackles in her left axillary region. After accumulating a 12 pack-yr smoking history, she had quit smoking 15 yrs earlier. She had immigrated to Canada from …

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 high-resolution 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.

Measurement and repeatability of interrupter resistance in unsedated newborn infants

Interrupter resistance (R(int)) is a useful measure of airway caliber in young children, but has not been well characterized in infants-in whom there are concerns about the accurate measurement of driving pressure. This study aimed to assess the feasibility and repeatability of measuring R(int) in unsedated newborn infants, and to explore alternative algorithms for calculating driving pressure. R(int) measurement was attempted in 28 healthy term newborn infants during natural sleep using the MicroRint device. Paired R(int) measurements were achieved in 24 infants, but after screening of waveforms only 15 infants had at least 5 technically acceptable waveforms on both measurements. R(int) values obtained were comparable with reported values for airflow resistance in newborns using other methods. However, the repeatability coefficient (CR) was much higher than reported values in preschool children using standard back-extrapolation algorithms, with CR 2.47 KPa L(-1) sec (unscreened) and 2.93 KPa L(-1) sec (screened). Other algorithms gave only marginally better repeatability, with all CR values over 50% of the mean R(int) value. Using current commercially available equipment, R(int) is too poorly repeatable to be a reliable measurement of airflow resistance in newborn infants. Lower deadspace equipment is needed, but anatomical and physiological factors in the infant are also important.

Physiology of obesity and effects on lung function

In obese people, the presence of adipose tissue around the rib cage and abdomen and in the visceral cavity loads the chest wall and reduces functional residual capacity (FRC). The reduction in FRC and in expiratory reserve volume is detectable, even at a modest increase in weight. However, obesity has little direct effect on airway caliber. Spirometric variables decrease in proportion to lung volumes, but are rarely below the normal range, even in the extremely obese, while reductions in expiratory flows and increases in airway resistance are largely normalized by adjusting for lung volumes. Nevertheless, the reduction in FRC has consequences for other aspects of lung function. A low FRC increases the risk of both expiratory flow limitation and airway closure. Marked reductions in expiratory reserve volume may lead to abnormalities in ventilation distribution, with closure of airways in the dependent zones of the lung and ventilation perfusion inequalities. Greater airway closure during tidal breathing is associated with lower arterial oxygen saturation in some subjects, even though lung CO-diffusing capacity is normal or increased in the obese. Bronchoconstriction has the potential to enhance the effects of obesity on airway closure and thus on ventilation distribution. Thus obesity has effects on lung function that can reduce respiratory well-being, even in the absence of specific respiratory disease, and may also exaggerate the effects of existing airway disease.

Low-frequency assessment of airway and tissue mechanics in ventilated COPD patients

Low-frequency forced oscillations have increasingly been employed to characterize airway and tissue mechanics separately in the normal respiratory system and animal models of lung disease; however, few data are available on the use of this method in chronic obstructive pulmonary disease (COPD). We studied 30 intubated and mechanically ventilated patients (COPD, n = 9; acute exacerbation of COPD, n = 21) during short apneic intervals at different levels of positive end-expiratory pressure (PEEP), with small-amplitude forced oscillations between 0.4 and 4.8 Hz. In 16 patients, measurements were made before and after inhalation of fenoterol hydrobromide plus ipratropium bromide (Berodual). Newtonian resistance and coefficients of tissue resistance (G) and elastance (H) were estimated from the respiratory system impedance (Zrs) data by model fitting. Apart from some extremely high Zrs data obtained primarily at relatively low PEEP levels, the model yielded a reasonable partitioning of the airway and tissue parameters, and the inclusion of further parameters did not improve the model performance. With increasing PEEP, Newtonian resistance and the ratio G/H decreased, reflecting the volume dependence of the airway caliber and the improved homogeneity of the lungs, respectively. Bronchodilation after the administration of Berodual was also associated with simultaneous decreases in G and H, indicating recruitment of lung units. In conclusion, the measurement of low-frequency Zrs can be accomplished in ventilated COPD patients during short apneic periods and offers valuable information on the mechanical status of the airways and tissues.

Neurologic Aspects of Sleep Apnea: Is Obstructive Sleep Apnea a Neurologic Disorder?

The upper airway caliber is determined by afferent sensory input to the brainstem respiratory centers and efferent motor neural output to the upper airway structures. Upper airway caliber is altered in obstructive sleep apnea. The mechanosensory receptors of the upper airway are capable of responding to changes in airway pressure, airflow, temperature, and to the upper airway muscle tone itself. Application of topical anesthesia change chronic snorers in apneic patients during sleep and prolong sleep apnea in obstructive sleep apnea (OSA) patients. Respiratory-related evoked potential are significantly reduced in OSA patients during non-rapid eye movement sleep indicating a sleep-related blunted cortical response to inspiratory occlusion. Histologic investigations of palatopharyngeal muscles from OSA patients show evidence of motor neuron lesions and actual damage to the muscles. Currently demonstrated local neurologic impairment and lesions can explain the development of sleep apneas and hypopneas.

Noninflammatory mechanisms of airway hyper-responsiveness in bronchial asthma: an overview

Airway hyper-responsiveness (AHR) is a cardinal feature of asthma. Its absence has been considered useful in excluding asthma, whereas it may be present in other diseases such as atopic rhinitis and chronic obstructive pulmonary disease. AHR is often considered an epiphenomenon of airway inflammation. Actually, the response of airways to constrictor stimuli is modulated by a complex array of factors, some facilitating and others opposing airway narrowing. Thus, it has been suggested that AHR, and perhaps asthma, might be present even without or before the development of airway inflammation. We begin this review by highlighting some terminological and methodological issues concerning the measurement of AHR. Then we describe the neurohumoral mechanisms controlling airway tone. Finally, the pivotal role of airway smooth muscle and internal and external modulation of airway caliber in vivo are discussed in detail.

Bronchodilator effects of exercise hyperpnea and albuterol in mild-to-moderate asthma

In asthmatic patients, either bronchodilatation or bronchoconstriction may develop during exercise. In 18 patients with mild-to-moderate asthma, we conducted two studies with the aims to 1) quantify the bronchodilator effect of hyperpnea induced by incremental-load maximum exercise compared with effects of inhaled albuterol (study 1, n=10) and 2) determine the time course of changes in airway caliber during prolonged constant-load exercise (study 2, n=8). In both studies, it was also investigated whether the bronchodilator effects of exercise hyperpnea and albuterol are additive. Changes in airway caliber were measured by changes in partial forced expiratory flow. In study 1, incremental-load exercise was associated with a bronchodilatation that was approximately 60% of the maximal bronchodilatation obtainable with 1,500 microg of albuterol. In study 2, constant-load exercise was associated with an initial moderate bronchodilatation and a late airway renarrowing. In both studies, premedication with inhaled albuterol (400 microg) promoted sustained bronchodilatation during exercise, which was additive to that caused by exercise hyperpnea. In conclusion, in mild-to-moderate asthmatic individuals, hyperpnea at peak exercise was associated with a potent yet not complete bronchodilatation. During constant-load exercise, a transient bronchodilatation was followed by airway renarrowing, suggesting prevalence of constrictor over dilator effects of hyperpnea. Finally, the bronchodilator effect of hyperpnea was additive to that of albuterol.

Measuring airway dimensions during bronchoscopy using anatomical optical coherence tomography

Airway dimensions are difficult to quantify bronchoscopically because of optical distortion and a limited ability to gauge depth. Anatomical optical coherence tomography (aOCT), a novel imaging technique, may overcome these limitations. This study evaluated the accuracy of aOCT against existing techniques in phantom, excised pig and in vivo human airways. Three comparative studies were performed: 1) micrometer-derived area measurements in 10 plastic tubes were compared with aOCT-derived area; 2) aOCT-derived airway compliance curves from excised pig airways were compared with curves derived using an endoscopic technique; and 3) airway dimensions from the trachea to subsegmental bronchi were measured using aOCT in four anaesthetised patients during bronchoscopy and compared with computed tomography (CT) measurements. Measurements in plastic tubes revealed aOCT to be accurate and reliable. In pig airways, aOCT-derived compliance measurements compared closely with endoscopic data. In human airways, dimensions measured with aOCT and CT correlated closely. Bland-Altman plots showed that aOCT diameter and area measurements were higher than CT measurements by 7.6% and 15.1%, respectively. Airway measurements using aOCT are accurate, reliable and compare favourably with existing imaging techniques. Using aOCT with conventional bronchoscopy allows real-time measurement of airway dimensions and could be useful clinically in settings where knowledge of airway calibre is required.

Morphometric bronchoscopy in adults with central airway obstruction: Case illustrations and review of the literature

The severity of airway narrowing impacts ventilatory function, quality of life, and choice of therapy for patients with central airway obstruction. The quantification of airway caliber remains a subjective estimate that depends on patient positioning, technique, and operator experience. In this article, we describe how morphometric bronchoscopy, a software processing method whereby bronchoscopic digital images are analyzed in order to measure airway lumen diameter, can be used to objectively quantify the degree of airway narrowing in adult patients with central airway obstruction.

Developmental Changes in Brainstem Neurons Regulating Lower Airway Caliber

Premature infants are at risk for lower airway obstruction; however, maturation of reflex pathways regulating lower airway patency is inadequately studied. We hypothesized that postnatal maturation causes developmental change in brainstem efferent airway-related vagal preganglionic neurons (AVPNs) within the rostral nucleus ambiguus (rNA) that project to the airways and in pulmonary afferent fibers that terminate in the nucleus tractus solitarius (NTS). Ferrets aged 7, 14, 21, and 42 d received intrapulmonary injection of cholera toxin (CT)-beta subunit, a transganglionic retrograde tracer. Five days later, their brainstem was processed for dual immunolabeling of CT-beta and the cholinergic marker, choline acetyl transferase. CT-beta-labeled AVPNs and CT-beta-labeled afferent fiber optical density (OD) were analyzed. There was a significantly higher CT-beta-labeled cell number within the rNA at the youngest compared with older ages. All efferent CT-beta-labeled cells expressed choline acetyl transferase. OD of CT-beta-labeled afferent fibers was also higher at 7 d compared with 14 d. We conclude that the number of efferent AVPNs and afferent fiber OD both diminish over the second postnatal week. We speculate that exposure to injurious agents in early postnatal life may inhibit natural remodeling and thereby enhance later vulnerability to airway hyperreactivity.

Pulmonary function and spinal cord injury

Injury to the cervical and upper thoracic spinal cord disrupts function of inspiratory and expiratory muscles, as reflected by reduction in spirometric and lung volume parameters and static mouth pressures. In association, subjects with tetraplegia have decreased chest wall and lung compliance, increased abdominal wall compliance, and rib cage stiffness with paradoxical chest wall movements, all of which contribute to an increase in the work of breathing. Expiratory muscle function is more compromised than inspiratory muscle function among subjects with tetraplegia and high paraplegia, which can result in ineffective cough and propensity to mucus retention and atelectasis. Subjects with tetraplegia also demonstrate heightened vagal activity with reduction in baseline airway caliber, findings attributed to loss of sympathetic innervation to the lungs. Significant increase in airway caliber following inhalation of ipratropium bromide, an anticholinergic agent, suggests that reduction in airway caliber is not due to acquired airway fibrosis stemming from repeated infections or to abnormal hysteresis secondary to chronic inability of subjects to inhale to predicted total lung capacity. Reduced baseline airway caliber possibly explains why subjects with tetraplegia exhibit airway hyperresponsiveness to methacholine and ultrasonically nebulized distilled water. While it has been well demonstrated that bilateral phrenic nerve pacing or stimulation through intramuscular diaphragmatic electrodes improves inspiratory muscle function, it remains unclear if inspiratory muscle training improves pulmonary function. Recent findings suggest that expiratory muscle training, electrical stimulation of expiratory muscles and administration of a long-acting beta(2)-agonist (salmeterol) improve physiological parameters and cough. It is unknown if baseline bronchoconstriction in tetraplegia contributes to respiratory symptoms, of if the chronic administration of a bronchodilator reduces the work of breathing and/or improves respiratory symptoms. Less is known regarding the benefits of treatment of obstructive sleep apnea, despite evidence indicating that the prevalence of this condition in persons with tetraplegia is far greater than that encountered in able-bodied individuals.

Acute Renal Failure and Mechanical Ventilation: Reality or Myth?

Acute Renal Failure and Mechanical Ventilation: Reality or Myth?

Sputum eosinophilia: an early marker of bronchial response to occupational agents

False-negative responses to specific inhalation challenge (SIC) with occupational agents may occur. We explored whether assessing changes in sputum cell counts would help improve the identification of bronchial reactivity to occupational agents during SICs. The predictive value of the changes in sputum cell counts after a negative FEV(1) response to a first challenge exposure to an occupational agent was determined using the changes in airway calibre observed during repeated challenges as the 'gold standard'. The study included 68 subjects investigated for work-related asthma in a tertiary centre. After a control day, the subjects were challenged with the suspected occupational agent(s) for up to 2 h. All subjects who did not show an asthmatic reaction were re-challenged on the following day. Additional challenges were proposed to those who demonstrated a > or = 2% increase in sputum eosinophils or an increase in nonspecific bronchial hyperresponsiveness to histamine after the second challenge day. Six of the 35 subjects without changes in FEV(1) on the first challenge developed an asthmatic reaction on subsequent challenges. ROC analysis revealed that a >3% increase in sputum eosinophils at the end of the first challenge day was the most accurate parameter for predicting the development of an asthmatic response on subsequent challenges with a sensitivity of 67% and a specificity of 97%. An increase in sputum eosinophils is an early marker of specific bronchial reactivity to occupational agents, which may help to identify subjects who will develop an asthmatic reaction only after repeated exposure.

School age outcome of hospitalisation with respiratory syncytial virus infection of prematurely born infants

Background:Hospitalisation due to respiratory syncytial virus (RSV) infection in the first 2 years after birth has been associated with increased healthcare utilisation and associated costs up to 5 years of...

Urban Residence Is Associated With Bronchial Hyperresponsiveness in Italian General Population Samples

The role of different risk factors for bronchial hyperresponsiveness (BHR), such as gender, atopy, IgE, and environmental factors (smoking, occupational exposure, infections), has been described. Indoor and outdoor pollution play an important role too, but few studies have analyzed the association with BHR. The aim of this study was to assess the effect of urban residence on BHR. We studied two general population samples enrolled in two cross-sectional epidemiological studies performed in Northern Italy (Po Delta, rural area) and Central Italy (Pisa, urban area). We analyzed 2,760 subjects (age range, 8 to 74 years). We performed analysis of variance and logistic regression analysis using ln slope of the dose-response curve of the methacholine challenge test as dependent variable, and sex, age, smoking habits, respiratory symptoms, skin-prick test results, IgE value, residence, and airway caliber as independent variables. The mean value of ln slope of the dose-response curve adjusted for initial airways caliber (by baseline FEV(1) percentage of predicted value) was significantly higher in female subjects, in smokers, in subjects with respiratory symptoms, in younger and older ages, in subjects with high values of IgE, and in subjects with positive skin-prick test results. After controlling for the independent effects of all these variables, living in urban area was an independent risk factor for having BHR (odds ratio, 1.41; 95% confidence interval, 1.13 to 1.76). Living in urban area is a risk factor for increased bronchial responsiveness.