Delayed distension of contracted airways with lung inflation in vivo

A deep inspiratory sigh is one of the most severe dynamic stresses that lungs normally experience. It typically is a very transient phenomenon, normally lasting only about 2 to 3 s. The airway response to a deep inspiration has been shown to be different in asthmatic and normal individuals. When airway smooth muscle (ASM) is contracted in normal subjects, a deep inspiration results in a subsequent dilation of the airways. However, in asthmatic subjects, a deep inspiration often results in little change in airway function, and sometimes results in an even further contraction of ASM. The mechanism underlying this difference depends on the dynamic behavior of both ASM and the lung parenchyma. If the contracted muscle had slower dynamic responses than the lung parenchyma, the timing of the deep inspiratory maneuver could affect the airway response. In the present study, we designed an experiment to determine how well matched the dynamic response is of airways to that of the lung parenchyma. The results clearly demonstrate that airways contracted with methacholine dilate at about a rate four times slower than that of the lung parenchyma during rapid lung inflation and deflation. This effect may play a role in the unique response of asthmatic subjects to deep inspiration. The mechanism of this dynamic slowness of contracted airways probably involves intrinsic properties of the smooth-muscle contractile processes.     

High-resolution computed tomographic evaluation of airway distensibility and the effects of lung inflation on airway caliber in healthy subjects and individuals with asthma

The effects of a deep inspiration (DI) in individuals with asthma differ from those observed in healthy subjects. It has been postulated that the beneficial effect of lung inflation is mediated by airway stretch. One hypothesis to explain the defects in the function of lung inflation in asthma is that a DI may be unable to stretch the airways. This may result from attenuation of the tethering forces between the airways and the surrounding parenchyma. In the current study, we used high-resolution computed tomography (HRCT) to examine the ability of a DI to distend the airways of subjects with asthma (n = 10) compared with healthy subjects (n = 9) at baseline and after increasing airway tone with methacholine (MCh). We found that both at baseline and after the induction of smooth muscle tone with MCh, a DI distended the airways of healthy and asthmatic subjects to a similar extent, indicating that abnormal interdependence between the lung parenchyma and the airways is unlikely to play a major role in the loss or attenuation of the beneficial effect of lung inflation that characterizes asthma. Furthermore, we observed that after constriction had already been induced by MCh, following a DI, bronchodilation occurred in the healthy subjects but further bronchoconstriction occurred in the subjects with asthma. Our findings suggest that an abnormal excitation contraction mechanism in the airway smooth muscle of subjects with mild asthma counteracts the bronchodilatory effect of a DI. Therefore, the mechanism for reduced bronchodilation after DIs in subjects with mild asthma could be intrinsic to the airway smooth muscle.     

Effect of bronchial thermoplasty on airway distensibility.

Recent studies have reported that the application of thermal energy delivered through a bronchoscope (bronchial thermoplasty) impairs the ability of airways to narrow in response to methacholine. How such altered smooth muscle affects the response of airways to lung inflation may have important clinical implications, particularly as it relates to the abnormal response of asthmatic subjects to lung inflation and deep inspiration. The aim of this study was to examine whether bronchial thermoplasty affected airway distension with lung inflation in relaxed and contracted airways. A total of 230 airways were studied, ranging 2.5-15 mm, in six dogs. These airways were divided into two groups: an untreated (control) population and a bronchial thermoplasty-treated population. Prior to treatment, the airway pressure-area curves in the two groups of airways were identical. In contrast, the relaxed and contracted airway pressure-area curves in treated airways were shifted upward at all points, showing increased airway area at both 3 and 5 weeks post-treatment. In conclusion, these results show that reducing that amount of functional smooth muscle with bronchial thermoplasty leads to increased airway size in both relaxed and contracted states over a normal range of inflation pressures.     

Mechanisms of limited airway dimension with lung inflation

Airways distend with each inspiration, while a sigh or deep inspiration (DI) leads to a significant or a maximum distension of the airways. Distension of the airways is thought to play an important role in maintaining airway patency. Limited distension of the airways with lung inflation may be a major factor in certain lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). High resolution computed tomography (HRCT) has gained wide acceptance as a diagnostic and investigational radiological tool for the evaluation of airway function. HRCT has been used to measure dynamic changes in airway caliber in vivo that are not detectable by conventional global lung measurements such as airway and lung resistance. HRCT is uniquely capable of imaging and quantifying airway size at different lung volumes. The current paper reviews the use of HRCT to examine the role of lung inflation on airway distension in animal models, and discusses potential mechanisms for limited distension of the airways with lung inflation in individuals with asthma and COPD.     

An overview of the anatomy and physiology of slowly adapting pulmonary stretch receptors

Since the original work of by Hering and Breuer in 1868 numerous studies have demonstrated that slowly adapting pulmonary stretch receptors (SARs) are the lung vagal afferents responsible for eliciting the reflexes evoked by moderate lung inflation. SARs play a role in controlling breathing pattern, airway smooth muscle tone, systemic vascular resistance and heart rate. Both anatomical and physiological studies support the contention that SARs, by their close association with airway smooth muscle, continuously sense the tension within the myoelastic components of the airways caused by lung inflation, smooth muscle contraction and/or tethering of small intrapulmonary airways to the lung parenchyma. In addition, intrapulmonary SAR discharge activity is sensitive to changes in P(CO2) within the physiological range. Despite this extensive characterization of SARs, their role in determining breathing pattern and airway tone in individuals with respiratory diseases is only recently being appreciated.     

Physiological assessment of inflammation in the peripheral lung of asthmatic patients

Even the asymptomatic asthmatic person with normal lung function may have peripheral airway obstruction and inflammation along with hyperresponsiveness to nonspecific challenges. The airway caliber change induced immediately following a deep inhalation (DI) appears to relate to the mechanism (inflammation vs. smooth muscle constriction) and site (peripheral vs. more central) of obstruction and the degree of hyperresponsiveness. Data are presented and reviewed that support the notion that relative hysteresis of parenchyma (including peripheral airways and alveolar ducts) and airways (more centrally located, conducting airways) can explain the magnitude and sign of airway caliber change that follow a DI in asthmatic subjects.     

Physiological assessment of inflammation in the peripheral lung of asthmatic patients

Even the asymptomatic asthmatic person with normal lung function may have peripheral airway obstruction and inflammation along with hyperresponsiveness to nonspecific challenges. The airway caliber change induced immediately following a deep inhalation (DI) appears to relate to the mechanism (inflammation vs. smooth muscle constriction) and site (peripheral vs. more central) of obstruction and the degree of hyperresponsiveness. Data are presented and reviewed that support the notion that relative hysteresis of parenchyma (including peripheral airways and alveolar ducts) and airways (more centrally located, conducting airways) can explain the magnitude and sign of airway caliber change that follow a DI in asthmatic subjects.     

Influence of lung inflation on the elastic properties of intra-and extrapulmonary airways in man.

In excised human lungs, the proximal intrapulmonary airways and distal extrapulmonary airways were isolated in situ, by means of the technique of Takishima el al. (1975), and submitted to varying transmural pressures at constant lung inflation. Both intra-and extrapulmonary airways became stiffer, i.e. showed a decreased collapsibility, at higher levels of lung inflation. The altered mechanical behavior of the intrapulmonary airways with lung inflation, observed also by Hughes et al. (1974) and Takishima et al. (1975), has been attributed to a tethering action of the lung parenchyma on these airways. The same mechanism may be operating on the distal extrapulmonary airways, to the extent that the pleura and hilar structures transmit the stresses of the lung parenchyma. Alternatively, the elongation of the bronchi occurring during lung inflation might be responsible for their increasing resistance to collapse with lung volume. A separate study showed, indeed, that stretching of the bronchi reduces their collapsibility.     

Time course and calcium dependence of sustained bronchoconstriction induced by deep inhalation in asthma.

We studied six asthmatic patients who showed a progressive decrease in FEV1 when successive forced expiratory maneuvers were performed at 1-min intervals. We determined the time course of changes in specific airway conductance following a single deep inhalation (DI) and the ratio of maximum expiratory flow at 40% of FVC from maximal and partial flow-volume curves (MEF40M/P) during a series of forced expiratory maneuvers. Specific airway conductance measured 3 s after DI was increased by 11 +/- 6 (SE)%, which was not significantly different from an increase of 23 +/- 8% observed in six healthy control subjects. Later (i.e., 10 to 40 s after DI) specific airway conductance was significantly less than the pre-DI value in asthmatic but not in healthy subjects. Mean FEV1 decreased significantly by 28% from the first to the eighth forced expiratory maneuver performed during a period of 15 min, whereas MEF40M/P was not significantly changed and remained always significantly greater than 1. The voltage-dependent calcium channel antagonist nifedipine significantly prevented the reduction of FEV1 without affecting MEF40M/P. We conclude that, in some asthmatic individuals, DI may induce a transient bronchodilatation followed by a calcium-dependent sustained bronchoconstriction. We suggest that the initial bronchodilatation is due to the mechanical interdependence between airways and lung parenchyma, whereas the sustained bronchoconstriction is due to contraction of the airway smooth muscle.     

The mechanism of deep inspiration-induced bronchoprotection: evidence from a mouse model

In healthy individuals, deep inspirations (DIs) taken prior to a bronchial challenge reduce the bronchoconstrictor response, which is termed "bronchoprotection". The mechanism(s) of DI-induced bronchoprotection is unclear. The forced oscillation technique was used to assess the effect of prior DI on subsequent bronchoconstriction to methacholine (MCh) in BALB/c mice. We assessed likely mechanisms for the bronchoprotective effects of DI including reduced airway narrowing (from changes in airway resistance) and/or closure (changes in tissue elastance) and enhanced bronchodilation to a subsequent DI (% reversal in airway narrowing). DI prior to MCh challenge: 1) did not reduce but instead enhanced airway narrowing (p<0.05); 2) increased ventilation heterogeneity (p<0.05); 3) enhanced the subsequent bronchodilatory response to DI (p<0.05); and 4) reduced tissue elastance (p<0.05), suggesting opening of closed airways or alveoli units. Our findings suggest that DI prior to MCh challenge may elicit a series of changes, some of which are beneficial to respiratory function (enhanced bronchodilation), while others place greater load on the system (enhanced bronchoconstriction and ventilation heterogeneity). It is proposed that the relative magnitudes of these opposing physiological and mechanical effects will determine the net effect on respiratory function in health and disease.     

Airway response to deep inspiration: role of nitric oxide.

Deep inspirations (DI) have been shown to have both bronchoprotective and bronchodilator effects in healthy subjects. The bronchodilator effects of a DI appear to be impaired in asthmatics compared with healthy subjects. This study investigated the role of nitric oxide (NO) in the bronchodilator role of a DI. In five anaesthetised and ventilated dogs, high-resolution computed tomography was used to measure the changes in airway size after a small (25 cmH2O) and large (45 cmH2O) DI before and after administering NG-nitro-L-arginine methyl ester to block NO synthesis. The depth of the inspiratory manoeuvre during a deep inspiration determined the subsequent qualitative behaviour of the airway response. Inflation to relatively high pressure resulted in airway dilation, whereas one to lower pressure leads to airway constriction. When NG-nitro-L-arginine methyl ester was administered, both a large and a small deep inspiration resulted in subsequent airway constriction. These results support the idea that nitric oxide may be a potential bronchoprotective agent in the airways.     

Advances in the study of infant lung function: forced expiratory maneuvers from an increased lung volume

Forced expiratory maneuvers from an increased lung volume in infants date from 1989 and consist of raising the inspiratory volume by applying a specific inflation pressure until a level close to the total lung capacity is reached. The chest and abdomen are then compressed by means of an inflatable jacket in order to obtain a forced expiratory flow-volume curve similar to that obtained for an adult. Forced expiration from an increased lung volume in infants is useful, just as the maneuver is in older patients, for studying airway function, diagnosing obstructive diseases early, and assessing response to treatment. The objective of this review is to provide information on the physiological bases and technical aspects of a lung function test that has proven highly useful for the study of the airways of healthy infants as well as those with respiratory diseases.     

The effect of the minimal deflation pressure on lung mechanics in isolated rabbit lungs

Alterations in the PV relationships of isolated rabbit lungs which are dependent on the minimal deflation pressure (Pmin) have been studied. When Pmin remains positive both inflation and deflation limbs of the PV loop are shifted toward lower transpulmonary (P₁) pressures throughout most of the cycle. In addition, Pmin(+) conditions eliminate the deflation inflection and increase deflation compliance at low and mid-lung volumes. Results from indicator washout and spontaneous deflation reveal that Pmin(+) conditions produce a more even inflation of the lung parenchyma and dilate airways at low lung volumes. These effects cause a stabilization of the parenchyma and a delay in airway closure resulting in the increased deflation compliance and a decrease in the trapped gas volume during Pmin(+) conditions. The relevance of Pmin(+) and (?) conditions are discussed for several clinical conditions.     

Reduction in bronchodilation following a deep inhalation is poorly related to airway inflammation in asthma.

In patients with bronchial asthma, forced expiratory flows are differently sensitive to a previous volume history. A reduced ability of a deep inhalation (DI) to dilate obstructed airways has been hypothesized to be a physiological marker for the degree of airway responsiveness and to relate to the presence and magnitude of inflammation in the lung, even in mild stable asthma. However, there are at present doubts as to whether functional changes could be used as a substitute for airway inflammation studies. In order to investigate the interrelations among airway inflammation, bronchial hyperresponsiveness and effects of volume history, 58 consecutive asthmatics with mild to moderate asthma were studied. The effects of DI were assessed as the isovolumic ratio of flows from forced expiratory manoeuvres started from maximal (M) or partial (P) lung inflation. Airway inflammation was assessed by using induced sputum. Sputum was analysed for total and differential cell counts, and levels of eosinophil cationic protein (ECP) which reflects eosinophil activation. Airway responsiveness was assessed as the provocative concentration of histamine which caused a 20% fall in forced expiratory volume in one second (FEV1) from control (PC20). The M/P ratio was significantly related to ECP (r=-0.31, p<0.03) and eosinophils (r=-0.29, p<0.03), FEV1/vital capacity (VC) (r=0.32; p<0.01), clinical score (r=-0.33; p<0.03) and age (r=-0.41; p<0.0001). In a stepwise multiple regression analysis including age, score, baseline lung function, ECP, number of eosinophils and the response to beta2-agonist, age (p<0.037) predicted a small amount of the variance in M/P ratio (r2=0.12). It is concluded that volume history response is substantially independent of both sputum outcomes (inflammatory cell number and eosinophil cationic protein) and bronchial hyperresponsiveness; rather it seems to be associated with anthropometric characteristics. Functional aspects do not provide information on eosinophilic, probably central, airway inflammation.     

Pathology and pathophysiology of chronic obstructive pulmonary disease

A variety of pathological changes have been observed in the central airways, peripheral airways and lung parenchyma of patients with chronic obstructive pulmonary disease (COPD). The characteristic changes in the central airways include inflammatory cellular infiltration into the airway wall and mucous gland enlargement. In the peripheral airways, various morphological changes are observed, including mucous plugging, epithelial abnormalities, inflammatory cellular infiltrates, fibrosis and distortion; these changes lead to airway narrowing. In the lung parenchyma, emphysema defined as alveolar destruction and airspace enlargement is present. Although the major sites of airflow limitation in patients with COPD are most likely the peripheral airways, lesions in both the peripheral airways and the lung parenchyma contribute to chronic airflow limitations.     

Mechanism of increased collateral airway resistance during inhomogeneous inflation of excised dog lungs

Collateral airway resistance was measured during inflation of an excised lung lobe or a segment within the lobe. Gas blown into the outer lumen of a double lumen catheter (Vcoll) inflated the segment and exited via collateral airways. Pressure at the catheter tip (Pct) was measured through the inner lumen of the catheter, and transpulmonary pressure (Pao) was measured at the lobar bronchus. A pleural capsule measured pressure in the segmental subpleural alveoli (Ps). The segment was inflated with helium (He), air, or sulfurhexafluoride; the lobe was ventilated with air. Collateral airway resistance [Rcoll = (Pct-Pao)/Vcoll], intrasegmental airway resistance [Rs = (Pct-Ps)/Vcoll], and resistance of airways passing through the segment-lobar interface [Ri = (Ps-Pao)/Vcoll] were calculated. Rcoll, Rs, and Ri were decreased by lobar inflation and increased by segment inflation. The latter increase was due to nonlaminar flow in intrasegmental airways. The major resistance was Ri when Vcoll was laminar or transitional. Moody plots suggested that lobar inflation caused intrasegmental airway dilation whereas segment inflation did not affect segment airway geometry.     

Pathogenesis of small airways in asthma

Asthma is a lung disease characterized by inflammation and remodeling of the airways. It is now widely accepted that airway inflammation and remodeling occur not only in the central airways but also in the small airways and even in the lung parenchyma. Inflammation of the distal lung can be observed even in mild asthmatics with normal or noncompromised lung function. Moreover, the small airways and the lung parenchyma can produce many Th2 cytokines and chemokines involved in initiation and perpetuation of the inflammatory process. In addition, the distal parts of the bronchial tree have been recognized as a predominant site of airflow obstruction in many asthmatics. In fact, the inflammation at this distal site has been described as more severe when compared to the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance, highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease.     

Pathophysiology of airflow limitation in chronic obstructive pulmonary disease

The airflow limitation that defines chronic obstructive pulmonary disease (COPD) is the result of a prolonged time constant for lung emptying, caused by increased resistance of the small conducting airways and increased compliance of the lung as a result of emphysematous destruction. These lesions are associated with a chronic innate and adaptive inflammatory immune response of the host to a lifetime exposure to inhaled toxic gases and particles. Processes contributing to obstruction in the small conducting airways include disruption of the epithelial barrier, interference with mucociliary clearance apparatus that results in accumulation of inflammatory mucous exudates in the small airway lumen, infiltration of the airway walls by inflammatory cells, and deposition of connective tissue in the airway wall. This remodelling and repair thickens the airway walls, reduces lumen calibre, and restricts the normal increase in calibre produced by lung inflation. Emphysematous lung destruction is associated with an infiltration of the same type of inflammatory cells found in the airways. The centrilobular pattern of emphysematous destruction is most closely associated with cigarette smoking, and although it is initially focused on respiratory bronchioles, separate lesions coalesce to destroy large volumes of lung tissue. The panacinar pattern of emphysema is characterised by a more even involvement of the acinus and is associated with alpha1 antitrypsin deficiency. The technology needed to diagnose and quantitate the individual small airway and emphysema phenotypes present in people with COPD is being developed, and should prove helpful in the assessment of therapeutic interventions designed to modify the progress of either phenotype.     

Pharmacologic responsiveness of rat parenchymal strips, bronchi, and bronchioles

It has been inferred from previous studies that leukotrienes C4 and D4 preferentially exhibit their effects on peripheral airways. Thus we used LTC4 to examine the responsiveness of parenchymal strips, lung preparations often used as in vitro models of airway function, and to compare the responses with those observed in a preparation of isolated peripheral airways. In these studies, the effects of LTC4 on isolated bronchioles of the rat were compared to responses observed in parenchymal strips and primary intrapulmonary bronchi. Parenchymal strips contracted in response to increasing concentrations of LTC4 and to a single concentration of bethanechol. When the maximum responses were normalized to that induced by membrane depolarization, it was found that the parenchymal strip was more responsive to the leukotriene. Primary intrapulmonary bronchi similarly contracted in response to LTC4; however, the intrapulmonary bronchi were much more responsive to bethanechol than to the leukotriene. The bronchioles were not responsive to LTC4 but did contract in response to membrane depolarization and on exposure to bethanechol. When normalized, the responsiveness of the bronchiole to bethanechol was significantly greater than the responsiveness of the bronchi to this agonist. Thus contraction of the rat parenchymal strip to LTC4 cannot be attributed to the direct effects of this agonist on bronchiolar smooth muscle. We conclude that the bronchiole of the rat is not responsive to LTC4 and that the contractions observed in the parenchymal strip in response to this agonist must result from a mechanism other than direct action of LTC4 on peripheral airway smooth muscle.     

Limitation of maximal bronchoconstriction in living dogs.

Fourteen dogs were studied to determine whether (1) interdependence between airways and parenchyma can limit maximal bronchoconstriction under static conditions in vivo, and (2) stretching of airway smooth muscle during tidal breathing can attenuate muscle shortening and account for the limited bronchoconstriction previously observed in response to increasing doses of methacholine (MCh). In six dogs the left lung was ventilated while 50% MCh was nebulized into the airways of the right lower lobe (RLL) held at constant transpulmonary pressures (PL). Airway closure, as assessed by an alveolar capsule technique during small oscillations in lobar volume, occurred at PL less than or equal to 7.5 cm H2O. To assess the effects of tidal breathing, pulmonary resistance (RL) was measured in four dogs after MCh nebulization into the RLL during tidal breathing while the left lung was separately ventilated. In another four dogs the whole lung was challenged with MCh. At each MCh concentration, RL values in the RLL were much higher than in the whole lungs (30-fold at the highest MCh concentration), showing that maximal bronchoconstriction in response to MCh is much greater in the RLL than in the whole lung. We conclude that neither interdependence nor tidal breathing can fully explain limited maximal bronchoconstriction in living dogs.