Bronchodilatory effect of deep inspiration is absent in subjects with mild COPD

STUDY OBJECTIVES: To investigate whether the bronchodilatory effect of deep inspiration is impaired in subjects with COPD. METHODS: We measured deep inspiration-induced bronchodilation in 19 patients with COPD and 17 healthy subjects (mean age, 67.8 +/- 7.1 years vs 62.5 +/- 9.3 years, respectively [+/- SEM]). Each subject underwent a series of single-dose methacholine provocations to induce at least a 15% reduction in inspiratory vital capacity (IVC). When this was achieved, subjects were asked to perform four consecutive deep inspirations, after which the IVC measurement was repeated and the percentage of bronchodilation by deep inspiration was calculated. RESULTS: The percentage of reduction in IVC from baseline prior to the deep inspirations did not differ between the two groups (COPD, 20.1 +/- 1.6%; healthy, 22.7 +/- 2.4%; p = 0.38); median single methacholine doses employed were 20 mg/mL (range, 0.025 to 75 mg/mL) and 25 mg/mL (range, 10 to 75 mg/mL), respectively (p = 0.19). Deep inspirations were not able to reverse bronchoconstriction in patients with COPD (bronchodilation, 3.9 +/- 2.6%; p = 0.15 by one-sample t test). Bronchodilation by deep inspiration was present in healthy subjects (13.7 +/- 3.0%, p = 0.0003), and was significantly higher than that of patient with COPD (p = 0.02). In patients with COPD, deep inspiration-induced bronchodilation correlated with the percentage of predicted transfer factor of the lung for carbon monoxide (r = 0.53, p = 0.05), but not with airway obstruction, as assessed by FEV(1) or FEV(1)/FVC. CONCLUSIONS: The bronchodilatory ability of deep inspiration is lost in mild COPD. We speculate that the absence of deep inspiration-induced bronchodilation contributes to the development and severity of chronic respiratory symptoms in patients with COPD.     

Airways dilate to simulated inspiratory but not expiratory manoeuvres

In a healthy human, deep inspirations produce bronchodilation of contracted airways, which probably occurs due to the transient distension of the airway smooth muscle (ASM). We hypothesised that deep expiratory manoeuvres also produce bronchodilation due to transient airway wall and ASM compression. We used porcine bronchial segments to assess the effects of deep inspirations, and maximal and partial expiration (submaximal) on airway calibre. Respiratory manoeuvres were simulated by varying transmural pressure using a hydrostatic pressure column: deep inspiration 5 to 30 cmH(2)O, maximal expiration 30 to -15 cmH(2)O, partial expiration 10 to -15 cmH(2)O; amidst a background of tidal oscillations, 5 to 10 cmH(2)O at 0.25 Hz. Changes in luminal cross-sectional area in carbachol-contracted airways were measured using video endoscopy. Deep inspirations produce an immediate bronchodilation (～40-60%, p=0.0076) that lasts for up to 1 min (p=0.0479). In comparison, after maximal expiration there was no immediate change in airway calibre; however, a delayed bronchodilatory response was observed from 4 s after the manoeuvre (p=0.0059) and persisted for up to 3 min (p=0.0182). Partial expiration had little or no effect or airway calibre. The results observed demonstrate that the airway wall dilates to deep inspiration manoeuvres but is unresponsive to deep expiratory manoeuvres.     

Absence of deep inspiration-induced bronchoprotection against inhaled allergen

Deep inspiration-induced bronchoprotection appears to be a major mechanism through which airway obstruction by spasmogens is avoided. Loss of bronchoprotection is associated with airway hyper-responsiveness. Individuals with allergic rhinitis and no airway hyperresponsiveness develop obstruction after allergen inhalation. To test the hypothesis that deep inspiration-induced bronchoprotection is not active against allergic reactions, we performed four single-dose bronchial challenges, two with methacholine and two with allergen, on 10 subjects with allergic rhinitis. Without deep inspirations, the methacholine-induced reduction in FEV1 from baseline was 36.9 +/- 3.6% (mean +/- SEM); this was attenuated to 15.0 +/- 2.0 when five deep inspirations preceded methacholine inhalation (p = 0.0001). When allergen was inhaled, the reduction in FEV1 was 24.7 +/- 2.9% and 28.8 +/- 6.4% without and with deep inspirations, respectively. We conclude that bronchoprotection by deep inspirations is absent against allergic reactions. Understanding the cause of this phenomenon may shed light into the pathogenesis of airway hyperresponsiveness in allergic asthma.     

Potential mechanism of hyperresponsive airways

It has been known for many years that the response of asthmatic subjects to a deep inspiration differs from that observed in normal healthy subjects. A deep inspiration causes a decrease in airway resistance in normal subjects, whereas asthmatics demonstrate either no change or a slight increase in airway resistance. It has been suggested by several investigators that the inability to dilate airways during lung inflation may be a primary defect in asthma. One study (Skloot and colleagues, J. Clin. Invest. 1995;96:2393- 2403) showed that in the absence of a deep inspiration during methacholine (MCh) challenge, normal subjects had a greatly exaggerated and sustained response to this agonist. It was suggested that asthmatic airways could be modeled by this condition in normal, subjects. Other investigators, however, suggest that there are more intrinsic differences between the responses to lung inflation in airways from asthmatic and normal subjects (Brusasco and colleagues, J. Appl. Physiol. 1999;87:567-573). Resolution of this controversy requires the ability to assess the responses of airways directly, but unfortunately conventional pulmonary function tests in human subjects are not specific enough to allow this evaluation. In the present study, we have performed experiments using a direct imaging approach that allows us to obtain measurements of airway and parenchymal dimensions that can be used to test the responses of individual airways to deep inspiration in vivo. Our results show that the presence of normal tidal stresses allows airway smooth muscle to respond normally to deep inspirations. Removing tidal stresses at FRC after MCh challenge is sufficient to change the normal dilatory response to deep inspiration into an abnormal one of contraction. Altered sensitivity of airway smooth muscle to normal tidal stresses thus may be operative in the development of the asthmatic pathology.     

Compliance, hysteresis, and collapsibility of human small airways.

We tested the hypothesis that airway wall dimensions are important determinants for the mechanical properties of airways. Lung tissue was obtained from 31 smokers with different degrees of chronic obstructive pulmonary disease (COPD) who were operated on for a solitary lung lesion. Segments of small airways (n = 35) were mounted on cannulas in an organ bath and inflated and deflated cyclically between +15 and -15 cm H(2)O. For each airway this was done at baseline, after methacholine, and after isoprenaline. Specific compliance (sCdyn), specific hysteresis (seta), and pressure at which the airways collapsed (Pcol) were calculated from each recording. Airway wall dimensions were measured morphometrically. Lung function parameters of airflow obstruction were correlated to sCdyn, seta, and Pcol. At baseline, after methacholine, and after isoprenaline sCdyn was 0.059, 0.052, and 0. 085 cm H(2)O(-)(1), seta was 13.5, 12.9, and 7.1%, and Pcol was -3.4, -3.5, and -1.9 cm H(2)O, respectively. Differences between sCdyn, seta, and Pcol after methacholine and after isoprenaline were highly significant (p < 0.001). Of all dimensions studied, smooth muscle area, but not total wall area, was the most important determinant for sCdyn and for seta after methacholine. Specific hysteresis at baseline correlated to residual volume as a fraction of total lung capacity (RV/TLC) (r = 0.5, p = 0.05) and, in the presence of methacholine, to FEV(1)/FVC (r = -0.68, p = 0.02) and RV/TLC (r = 0. 5, p = 0.05). We conclude that, in this study, smooth muscle area and smooth muscle tone, but not total wall area, are determinants for compliance, hysteresis, and collapsibility of isolated airways obtained from smokers.     

Airway remodeling: a comparison between fatal and nonfatal asthma.

BACKGROUND: Airway remodeling has been recently one of the main goals in asthma research because it has been implicated to influence airway behavior and evolution of asthma; hence, important in long-term followup of asthmatic patients. METHODS: Airways of fatal asthma (n=3), non-fatal asthma (n=3) and control cases (n=4) were studied using morphometry and immunohistochemical and H&E staining. RESULTS: The basement membrane was thicker in the cartilaginous and membranous airways of fatal and non-fatal asthma groups compared to the control group (p<0.05). Smooth muscle shortening was greater in airways of fatal asthma cases while submucosal gland area and mucus plug occupying ratio were greater in fatal asthma large airways compared to the two other groups (p<0.01). Increased intact and degranulated mast cells were observed in smooth muscle and in submucosal gland of fatal asthma airways (p<0.01) and were associated with greater degree of smooth muscle shortening and larger submucosal gland area, respectively. Eosinophil and EG2+ cell infiltrations were greatest in lamina propria of airways of fatal asthma than in nonfatal and control cases (p<0.01), but were not associated with any airway structural change. CONCLUSION: Increased infiltration of eosinophils in the lamina propria and mast cells in smooth muscle and submucosal glands may have a role in airway remodeling of fatal asthma airways but needs further investigation. Moreover, mast cells in cartilaginous airways may participate in the regulation of smooth muscle tone and mucous gland secretion and hyperplasia.     

Inhaled corticosteroids and the beneficial effect of deep inspiration in asthma

Deep inspiration-induced bronchoprotection and bronchodilation are impaired in asthma. We evaluated the effect of inhaled glucocorticosteroids on these phenomena. Two groups of subjects with asthma, 9 with moderate/severe hyperresponsiveness to methacholine, and 12 with mild/borderline hyperresponsiveness to methacholine, received inhaled fluticasone (880 microg daily) for 12 weeks. Serial bronchoprovocations were performed at Weeks 0, 6, and 12. The impact of deep inspirations on the airway response to methacholine was evaluated on the basis of inspiratory vital capacity and FEV(1). Fluticasone produced a wide spectrum of changes in the beneficial effects of deep inspiration, but the mean changes were not significant. The magnitude of the steroid-induced changes in bronchoprotection by deep inspiration correlated with baseline log PC(20) (the provocative concentration of methacholine causing a 20% fall in FEV(1); higher log PC(20) predicted improvement of the deep inspiration effect). The steroid-induced changes led to the emergence of strong positive correlations between the effects of deep inspiration and the methacholine log PC(20) that did not exist at baseline. We conclude that deep inspiration-induced bronchoprotection can be restored by inhaled glucocorticosteroids only in individuals with mild hyperresponsiveness. After steroid treatment, the beneficial effects of deep inspiration become significant determinants of the magnitude of airway hyperresponsiveness.     

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.     

Mast cells in COPD airways: relationship to bronchodilator responsiveness and angiogenesis

We have investigated whether mast cells are associated with bronchodilator responsiveness and airway vascular changes in chronic obstructive pulmonary disease (COPD) airways. We have previously shown that the reticular basement membrane is hypervascular and the lamina propria is hypovascular in COPD. Bronchial biopsies from 32 COPD subjects, 15 smokers with normal lung function and 17 controls, were immunostained for factor VIII, mast cell tryptase and chymase antibodies. Mast cells in the airway smooth muscle, the reticular basement membrane and the underlying lamina propria were quantitated. 41% of COPD subjects had significant bronchodilator responsiveness, but this was not related to smooth muscle mast cell numbers. The reticular basement membrane had greater mast cell density in all groups compared with controls (p<0.01). In this compartment, perivascular mast cell density was related to hypervascularity. Lamina propria mast cell density was increased only in COPD (p<0.05). Perivascular mast cell density in the lamina propria was not related to its decreased vessel density. Bronchodilator responsiveness in COPD is not related to large airway smooth muscle mast cells of either type; both reticular basement membrane and lamina propria mast cells are increased in COPD patients, and perivascular mast cells may be involved in increased angiogenesis in the reticular basement membrane.     

Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma.

There are few data regarding the potential effects of antiasthma treatment on indices of airway remodeling, such as the increased subepithelial airway vascularity in patients with asthma. We studied 45 symptomatic subjects with asthma who were receiving treatment with low dose inhaled corticosteroids (ICS) (range 200-500 microg twice a day) and 28 normal subjects without asthma as a control population. Subjects underwent bronchoscopy with airway biopsy and subjects with asthma were then randomized to receive supplementary inhaled salmeterol 50 microg twice a day, fluticasone propionate 100 microg twice a day, or placebo for 3 mo in addition to their baseline ICS. Biopsy of the airway was then repeated. The biopsies were analyzed for vascular structures in the subepithelial lamina propria. Sufficient biopsy material was available for analysis of vascularity in 34 of the subjects with asthma and 28 of the normal subjects. We confirmed that airways of subjects with asthma had a significant increase in the number of vessels/mm2 of lamina propria compared with airways of normal subjects (524 +/- 137 vessels/mm2, n = 34 versus 425 +/- 130 vessels/mm2, n = 28; p = 0.004). There was a decrease in the density of vessels of lamina propria after treatment only in the salmeterol group compared with baseline (before, 535 +/- 153 vessels/mm2 versus after, 400 +/- 142 vessels/mm2; n = 12; p = 0.04). There was no significant change within the fluticasone (n = 11) or placebo (n = 11) treatment groups, but also no significant differences between the groups. Notably, no treatment was associated with increased airway wall vascularity. The demonstrated fall in vessel number within the salmeterol-treated group may suggest an advantageous effect of long-acting beta2-agonists on this manifestation of airway remodeling over the 3-mo time scale of this study, which is complementary to the action of ICS on airway vascularity.     

Is a myogenic response involved in deep inspiration-induced bronchoconstriction in asthmatics?

The mechanisms by which a deep inspiration (DI) induces bronchoconstriction in some asthmatic patients remain unclear. As a calcium-dependent myogenic response could be involved, we examined the effect of a potent voltage-dependent calcium channel (VDC) antagonist, nifedipine (20 mg administered sublingually) versus placebo, on the DI-induced change in plethysmographic specific airway conductance (SGaw) in six asthmatic patients and six healthy controls both before and after a bronchial challenge with methacholine (MCh). In the asthmatic group, when compared to those receiving placebo, nifedipine significantly reduced the decrease in SGaw induced by the DI at baseline (-34.2 +/- 5.6 and -12.7 +/- 3.6%, respectively) but it had no significant effect on mean SGaw baseline values (0.096 +/- 0.018 and 0.075 +/- 0.015 cm H2O-1.s.-1, respectively). When airway tone was increased with MCh, the DI-induced change in SGaw was reduced and nifedipine then had no further effect. In the control group, nifedipine had no significant effect on the weak changes in SGaw induced by the DI before or after the bronchial challenge. We conclude that nifedipine reduces DI-induced bronchoconstriction only in subjects with asthma and without altering baseline tone in airway smooth muscle. We suggest that this effect of nifedipine could be explained by the existence of a myogenic response in asthma, caused by the conversion of airway smooth muscle from intermediate to single unit function.     

Effect of Inhaled Racemic and (R)-Albuterol on Airway Vascular Smooth Muscle Tone in Healthy and Asthmatic Subjects

Although the relative effect of racemic and (R)-albuterol on airway smooth muscle tone have been investigated in patients with airflow obstruction, the comparative effectiveness of these drugs in relaxing airway vascular smooth muscle is unknown. Therefore, we determined the actions of inhaled racemic and (R)-albuterol on airway mucosal blood flow (Qaw) normalized for anatomic dead space as an index of airway vascular smooth muscle tone in 11 healthy subjects and 10 subjects with mild asthma. We also monitored the forced expiratory volume in 1 second (FEV1) as an index of airway smooth muscle tone. Mean +/- SE baseline Qaw was 43.1 +/- 1.5 microl x min(-1) x ml(-1) in healthy subjects and 53.4 +/- 2.1 microl x min(-1) x ml(-1) in asthmatic subjects (p < 0.01). The corresponding values for FEV1 were 95.6 +/- 1.4 and 86.8 +/- 2.5% respectively, of predicted (p = 0.01). Racemic and (R)-albuterol caused a transient, dose-dependent increase of Qaw in healthy, but not in asthmatic subjects; the responses were not different between the two drugs. The FEV1 tended to increase more in asthmatics than in healthy subjects, again without a difference between the two drugs. These results show that racemic and (R)-albuterol have comparable effects on airway vascular smooth muscle and suggest that the blunted airway vascular smooth muscle response to albuterol in asthmatics is not related to (S)-albuterol.     

Bronchial thermoplasty for asthma

RATIONALE: Bronchial thermoplasty (BT) reduces the potential for smooth muscle-mediated bronchoconstriction by reducing the mass of smooth muscle in the walls of conducting airways. OBJECTIVES: This study was conducted to examine the safety and impact on lung function and airway responsiveness of BT over 2 yr. METHODS: The safety of BT was studied in 16 subjects with mild to moderate asthma. Baseline and 12-wk post-treatment measurements included spirometry, methacholine challenge, daily diary recordings of peak flow, symptoms, and medication usage. Subjects completed follow-up evaluations at 12 wk, 1 yr, and 2 yr. MEASUREMENTS AND MAIN RESULTS: The procedure was well tolerated; side effects were transient and typical of what is commonly observed after bronchoscopy. All subjects demonstrated improvement in airway responsiveness. The mean PC(20) increased by 2.37 +/- 1.72 (p < 0.001), 2.77 +/- 1.53 (p = 0.007), and 2.64 +/- 1.52 doublings (p < 0.001), at 12 wk, 1 yr, and 2 yr post-procedure, respectively. Data from daily diaries collected for 12 wk indicated significant improvements over baseline in symptom-free days (p = 0.015), morning peak flow (p = 0.01), and evening peak flow (p < or = 0.007). Spirometry measurements remained stable throughout the study period. CONCLUSIONS: BT is well tolerated in patients with asthma and results in decreased airway hyperresponsiveness that persists for at least 2 yr.     

Inspiratory muscle unloading by neurally adjusted ventilatory assist during maximal inspiratory efforts in healthy subjects

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) is a mode of mechanical ventilation in which the ventilator is controlled by the electrical activity of the diaphragm (EAdi). During maximal inspirations, the pressure delivered can theoretically reach extreme levels that may cause harm to the lungs. The aims of this study were to evaluate whether NAVA could efficiently unload the respiratory muscles during maximal inspiratory efforts, and if a high level of NAVA would suppress EAdi without increasing lung-distending pressures. METHOD: In awake healthy subjects (n = 9), NAVA was applied at increasing levels in a stepwise fashion during quiet breathing and maximal inspirations. EAdi and airway pressure (Paw), esophageal pressure (Pes), and gastric pressure, flow, and volume were measured. RESULTS: During maximal inspirations with a high NAVA level, peak Paw was 37.1 +/- 11.0 cm H(2)O (mean +/- SD). This reduced Pes deflections from - 14.2 +/- 2.7 to 2.3 +/- 2.3 cm H(2)O (p < 0.001) and EAdi to 43 +/- 7% (p < 0.001), compared to maximal inspirations with no assist. At high NAVA levels, inspiratory capacity showed a modest increase of 11 +/- 11% (p = 0.024). CONCLUSION: In healthy subjects, NAVA can safely and efficiently unload the respiratory muscles during maximal inspiratory maneuvers, without failing to cycle-off ventilatory assist and without causing excessive lung distention. Despite maximal unloading of the diaphragm at high levels of NAVA, EAdi is still present and able to control the ventilator.     

The effect of hyperinflation on rib cage-abdominal motion.

Abnormalities of rib cage-abdominal motion are common in patients with chronic obstructive pulmonary disease (COPD), but the basis of the abnormal motion has not been completely determined. Although airway obstruction has been shown to be a major factor in causing abnormal chest wall motion, the effect of hyperinflation (which has numerous adverse effects on respiratory muscle function) has not been systematically examined. We induced graded levels of hyperinflation in six healthy volunteers using continuous positive airway pressure (CPAP) levels of 10, 20, and 30 cm H2O. Chest wall motion was measured by a calibrated inductive plethysmograph. Rib cage-abdominal asynchrony and paradox were quantitated by the Konno-Mead method of analysis. CPAP levels of 10, 20, and 20 cm H2O produced increases in end-expiratory lung volume of 0.98 +/- 0.14 (SE), 1.90 +/- 0.31, and 2.42 +/- 0.37 L, respectively (p < 0.0001). This corresponded to an increase in the ratio of functional residual capacity to predicted total lung capacity from 0.38 +/- 0.08 at baseline to 0.74 +/- 0.14 at 30 cm H2O CPAP-comparable to that seen in patients with COPD. Hyperinflation induced an increase in inspiratory abdominal paradox, 1.0 +/- 0.7% at baseline versus 3.6 +/- 1.7% at 30 cm H2O (p < 0.05), but this is unlikely to be clinically significant. A significant increase in asynchrony or rib cage paradox did not develop with hyperinflation. In conclusion, the primary factor contributing to abnormal chest wall motion in patients with COPD is likely to be increased airway resistance, and hyperinflation makes only a minor contribution.     

Respiratory and skeletal muscles in hypogonadal men with chronic obstructive pulmonary disease

Hypogonadism, found in about one-third of patients with chronic obstructive pulmonary disease (COPD), has potential for decreasing muscle mass and muscle performance. Compared with eugonadal patients, we hypothesized that hypogonadal patients with COPD have decreased respiratory and skeletal muscle performance. Nineteen hypogonadal and 20 eugonadal men with COPD (FEV(1) 1.14 +/- 0.08 and 1.17 +/- 0.11 L [standard error], respectively) were studied. Diaphragmatic contractility, assessed as transdiaphragmatic twitch pressure generated by phrenic nerve stimulation, was similar in hypogonadal and eugonadal patients: 20.6 +/- 2.2 and 19.8 +/- 2.5 cm H(2)O, respectively. During progressive inspiratory threshold loading, hypogonadal and eugonadal patients had similar respiratory muscle endurance times (302 +/- 29 and 313 +/- 48 seconds, respectively) and airway pressure sustained during the last minute of loading (38.2 +/- 3.0 and 40.5 +/- 4.7 cm H(2)O, respectively) (similar to predicted values in healthy subjects). Hypogonadal and eugonadal patients had equivalent limb muscle strength and endurance. During cycle exercise to exhaustion, exercise performance, gas exchange, and respiratory muscle recruitment (estimated by esophageal and gastric pressure swings during tidal breathing) were similar in both groups. In conclusion, hypogonadism does not decrease respiratory or limb muscle performance and exercise capacity in men with moderate-to-severe COPD who, for the most part, are not underweight.     

Comparative effects of volume history on bronchoconstriction induced by hyperventilation and methacholine in asthmatic subjects

The aim of this study was to find out if bronchodilatation following deep inspiration can be induced by the inhalation of a "natural" stimulus (hyperventilation of cold dry air), and if the effect is similar to that induced by methacholine. After baseline assessment of lung resistance (RL), 10 asthmatic subjects were asked to inhale cold dry air for 3 min. RL was monitored continuously for 3-4 min, at which time subjects were asked to take a fast deep inspiration. After recovery, the manoeuvre was repeated and RL was reassessed. The manoeuvre was then repeated a third time. After functional recovery, progressive doses of methacholine were inhaled until the increase in RL was comparable to that obtained after hyperventilation (56 +/- 16% and 65 +/- 24%, respectively, mean +/- SD, NS). The same deep inspiration manoeuvre was repeated three times with recovery as after hyperventilation of cold dry air. Maximum changes in RL were not significantly different after each of the three manoeuvres for either type of bronchoconstriction. The mean fall in RL was 14.2 +/- 9.9% after hyperventilation and 16.4 +/- 10.5% after methacholine. There was a satisfactory correlation (r = 0.80, p less than 0.01) between the bronchodilatation after deep inspiration for both types of stimuli. We conclude that the bronchodilator effect of deep inspiration is no different using either a pharmacological stimulus (methacholine) or a "natural" stimulus (hyperventilation of unconditioned air). These results show that assessing the response to hyperventilation with manoeuvres requiring deep inspiration, forced expiratory volume in one second (FEV1) may alter airway tone in a way similar to pharmacological stimuli.     

Modification of histamine- and methacholine-induced bronchoconstriction by calcium antagonist gallopamil in asthmatics.

We studied the comparative modification of histamine- and methacholine-induced bronchoconstriction by a calcium antagonist, gallopamil, in 8 subjects with bronchial asthma. Dose-response curves to aerosolized methacholine or histamine were performed, without and following pretreatment with inhaled gallopamil (10 mg), on 6 different experiment days to determine the cumulative provocative dose (PD50) of each agonist in breath units which caused a 50% decrease in specific airway conductance (SGaw). Baseline values of SGaw were similar on different experiment days and gallopamil had no significant effect on SGaw. PD50 values for histamine on control and placebo days were 6.8 +/- 2.8 and 5.2 +/- 2.8 breath units (mean +/- SE), respectively. Pretreatment with gallopamil increased histamine PD50 to 19.8 +/- 7.5 breath units, which was significantly greater than on control and placebo days (p < 0.01). PD50 values for methacholine on control and placebo days were 9.5 +/- 5.6 and 8.8 +/- 5.8 breath units, respectively. Gallopamil pretreatment had no significant effect on methacholine-induced bronchoconstriction; methacholine PD50 increased to 13.4 +/- 5.5 breath units (p = NS). The mean dose ratio (ratio of PD50 for the agonist in the presence and absence of gallopamil) for histamine was 6.9, which was 3.7-fold higher than the dose ratio of 1.9 methacholine in the same subjects. These data suggest that gallopamil causes greater inhibition of histamine- versus methacholine-induced bronchoconstriction. This suggests that calcium influx in airway smooth muscle through voltage-dependent channels primarily occurs in response to histamine and not to methacholine.     

Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity

Little is known of the structural changes in mild asthma. We have studied the light and electron microscopic structure of lobar bronchial biopsies taken at fiberoptic bronchoscopy from 11 atopic asthmatics, four of whom were symptomatic and seven of whom were asymptomatic. The former and three of the latter had bronchial hyperresponsiveness to methacholine (PC20 less than 4 mg/ml). Quantitative comparisons were made with biopsies from ten control subjects with normal airway reactivity; five had hay fever and five were nonatopic healthy volunteers. Complete absence of surface epithelium was found in three cases of symptomatic asthma, and stratified squamous epithelium was present in the fourth. A biopsy from one of the healthy control subjects had also lost its surface epithelium. The degree of epithelial loss in all subjects correlated with the degree of airway reactivity (rs = 0.67, p less than 0.001). The reticular lamina of the epithelial basement membrane showed a trend toward thickening in the seven hyperreactive asthmatics (p less than 0.001: median test). There was a tendency to high numbers of inflammatory cells in the lamina propria, but not in the submucosa, of asthmatics, but the differences between groups did not achieve statistical significance. There were significant alterations (px2 less than 0.001) in the proportions of each type of inflammatory cell found in the lamina propria and submucosa of symptomatic asthmatics: an increase of irregularly shaped lymphocytes contributed most to the observed alteration. Where surface epithelium was present, intraepithelial lymphocytes formed the major proportion of intraepithelial "migratory" cells: 64% in normal control subjects, 78% in subjects with hay fever, and 87% in asymptomatic asthmatics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Difference between dosimeter and tidal breathing methacholine challenge: contributions of dose and deep inspiration bronchoprotection

BACKGROUND: Two bronchoprovocation methods are widely used. Compared to the tidal breathing method, the dosimeter method delivers approximately half the dose and involves five deep inhalations. Both the lower dose and the bronchoprotective deep inhalations contribute to the lesser airway response of the dosimeter. OBJECTIVE: To determine the relative role of dose and deep inspiration in the difference between the two methods. METHODS: Subjects with asthma (n = 24) underwent three methacholine challenges: a dosimeter challenge, a 2-min tidal breathing challenge (twice the dose), and a modified 2-min tidal breathing challenge (twice the dose plus five deep inhalations). RESULTS: The dosimeter method produced a nonsignificantly lower response than the modified tidal breathing method (p = 0.14). Both deep inhalation methods produced significantly less response than did the standard tidal breathing method (p = 0.011). In the 12 subjects with the most mild airway hyperresponsiveness (AHR), the differences between the deep inhalation method and the tidal breathing method were greater (p = 0.007). By contrast, deep inhalations produced no effect in the 12 subjects with greater AHR; the two tidal breathing methods produced identical results, while the dosimeter produced less response than either (p = 0.033). Six current asthmatics with mild airway responsiveness (tidal breathing method) had negative dosimeter methacholine challenge results. CONCLUSIONS: In subjects with moderate airway responsiveness, the difference between the methods is due to the difference in dose, whereas in subjects with mild AHR, deep inhalations had a large effect overwhelming the dose effect and producing false-negative methacholine challenge results in 25% of the subjects.