Heterogeneous airway tone in asthmatic subjects.

We examined the effect of volume history on the dynamic relationship between airways and lung parenchyma (relative hysteresis) in 20 asthmatic subjects. The acoustic reflection technique was employed to evaluate changes in airway cross-sectional areas during a slow continuous expiration from total lung capacity to residual volume and inspiration back to total lung capacity. Lung volume was measured continuously during this quasi-static maneuver. We studied three anatomic airway segments: extra- and intrathoracic tracheal and main bronchial segments. Plots of airway area vs. lung volume were obtained for each segment to assess the relative magnitude and direction of the airway and parenchymal hysteresis. We also performed maximal expiratory flow-volume and partial expiratory flow-volume curves and calculated the ratio of maximal to partial flow rates (M/P) at 30% of the vital capacity. We found that 10 subjects (group I) showed a significant predominance of airway over parenchymal hysteresis (P < 0.005) at the extra- and intrathoracic tracheal and main bronchial segments; these subjects had high M/P ratios [1.53 +/- 0.27 (SD)]. The other 10 subjects (group II) showed similar airway and parenchymal hysteresis for all three segments and significantly lower M/P ratios (1.16 +/- 0.20, P < 0.01). We conclude that the effect of volume history on the relative hysteresis of airway and lung parenchyma and M/P ratio at 30% of vital capacity in nonprovoked asthmatic subjects is variable. We suggest that our findings may result from heterogeneous airway tone in asthmatic subjects.     

Tracking variations in airway caliber by using total respiratory vs. airway resistance in healthy and asthmatic subjects.

An index of airway caliber can be tracked in near-real time by measuring airway resistance (Raw) as indicated by lung resistance at 8 Hz. These measurements require the placing of an esophageal balloon. The objective of this study was to establish whether total respiratory system resistance (Rrs) could be used rather than Raw to track airway caliber, thereby not requiring an esophageal balloon. Rrs includes the resistance of the chest wall (Rcw). We used a recursive least squares approach to track Raw and Rrs at 8 Hz in seven healthy and seven asthmatic subjects during tidal breathing and a deep inspiration (DI). In both subject groups, Rrs was significantly higher than Raw during tidal breathing at baseline and postchallenge. However, at total lung capacity, Raw and Rrs became equivalent. Measured with this approach, Rcw appears volume dependent, having a magnitude of 0.5-1.0 cmH2O. l-1. s during tidal breathing and decreasing to zero at total lung capacity. When resistances are converted to an effective diameter, Rrs data overestimate the increase in diameter during a DI. Simulation studies suggest that the decrease in apparent Rcw during a DI is a consequence of airway opening flow underestimating chest wall flow at increased lung volume. We conclude that the volume dependence of Rcw can bias the presumed net change in airway caliber during tidal breathing and a DI but would not distort assessment of maximum airway dilation.     

Adrenergic airway vascular smooth muscle responsiveness in healthy and asthmatic subjects.

The purpose of the present study was to determine the responsiveness of airway vascular smooth muscle (AVSM) as assessed by airway mucosal blood flow (Qaw) to inhaled methoxamine (alpha(1)-agonist; 0.6-2.3 mg) and albuterol (beta(2)-agonist; 0.2-1.2 mg) in healthy [n = 11; forced expiratory volume in 1 s, 92 +/- 4 (SE) % of predicted] and asthmatic (n = 11, mean forced expiratory volume in 1 s, 81 +/- 5%) adults. Mean baseline values for Qaw were 43.8 +/- 0.7 and 54.3 +/- 0.8 microl. min(-1). ml(-1) of anatomic dead space in healthy and asthmatic subjects, respectively (P < 0.05). After methoxamine inhalation, the maximal mean change in Qaw was -13.5 +/- 1.0 microl. min(-1). ml(-1) in asthmatic and -7.1 +/- 2.1 microl. min(-1). ml(-1) in healthy subjects (P < 0.05). After albuterol, the mean maximal change in Qaw was 3.0 +/- 0.8 microl. min(-1). ml(-1) in asthmatic and 14.0 +/- 1.1 microl. min(-1). ml(-1) in healthy subjects (P < 0.05). These results demonstrate that the contractile response of AVSM to alpha(1)-adrenoceptor activation is enhanced and the dilator response of AVSM to beta(2)-adrenoceptor activation is blunted in asthmatic subjects.     

IL-6 increases airway resistance in the rat

The end-inspiratory occlusion method was applied in anesthetized, paralyzed, positive pressure-ventilated rats to assess the possible effects of interleukin IL-6 on respiratory mechanics in normal rats. Measurements were made in control rats and in experimental animals before and after IL-6 intraperitoneal administration (15 ng/100 g), including static respiratory system elastance, the resistance to airflow and to the movement of respiratory system tissues, and the resistance due to lung stress–relaxation and mechanical inhomogeneity. Respiratory system hysteresis was also measured, and total mechanical breathing work rate and its elastic and resistive components calculated.Control rats did not exhibit alteration in respiratory mechanics during the observation period (30 min), while the experimental animals showed an increase in resistive pressure dissipations starting 15 min after IL-6 administration. Dose-dependent effects were also investigated.In a rather delayed effect, IL-6 increased the resistance to airflow and to the movement of respiratory system tissues, the resistance due to lung stress–relaxation and mechanical inhomogeneity, and the related resistive mechanical breathing work rate, and left the elastic pressure dissipation unaltered. The mechanisms by which IL-6 may contribute to the airways resistance increase which is seen in different respiratory diseases are likewise discussed.     

Deep breaths, methacholine, and airway narrowing in healthy and mild asthmatic subjects.

Deep breaths taken before inhalation of methacholine attenuate the decrease in forced expiratory volume in 1 s and forced vital capacity in healthy but not in asthmatic subjects. We investigated whether this difference also exists by using measurements not preceded by full inflation, i.e., airway conductance, functional residual capacity, as well as flow and residual volume from partial forced expiration. We found that five deep breaths preceding a single dose of methacholine 1) transiently attenuated the decrements in forced expiratory volume in 1 s and forced vital capacity in healthy (n = 8) but not in mild asthmatic (n = 10) subjects and 2) increased the areas under the curve of changes in parameters not preceded by a full inflation over 40 min, during which further deep breaths were prohibited, without significant difference between healthy (n = 6) and mild asthmatic (n = 16) subjects. In conclusion, a series of deep breaths preceding methacholine inhalation significantly enhances bronchoconstrictor response similarly in mild asthmatic and healthy subjects but facilitates bronchodilatation on further full inflation in the latter.     

Novel effects of PGF2 alpha on airway function in asthmatic subjects

The effects of inhaled prostaglandin F2 alpha (PGF2 alpha) have been examined in eight subjects with asthma. Incremental PGF2 alpha aerosol concentrations, ranging from 1 to 5,000 micrograms/ml, were administered at 15-min intervals. Plethysmographic specific airway conductance (sGaw), forced expiratory volume at 1 s (FEV1), and maximum expiratory flow at 50% vital capacity breathing air (Vmax50% air) and 80% He-20% O2 (Vmax50% He-O2) were measured after each dose and compared with saline control values. We observed unexpected triphasic dose-response characteristics, i.e., an initial decline in physiological variables at low concentrations (1-100 micrograms/ml), followed by improvement at intermediate concentrations (100-1,000 micrograms/ml) and a subsequent steep decline at high concentrations (1,000-5,000 micrograms/ml). Improvement in FEV1 and Vmax50% air between 100 and 1,000 micrograms/ml was associated with sGaw increases above control levels in six subjects and a significant fall in density-dependent index (Vmax50% He-O2/Vmax50% air) when compared with values before challenge and at low concentrations. Inhaled atropine (5 mg) improved prechallenge lung function but had no effect on PGF2 alpha dose-response characteristics. Intermediate PGF2 alpha concentrations given as a single dose consistently induced greater FEV1 reductions than the same concentration during graded dose challenges. Our findings are consistent with the demonstration of in vivo airway tachyphylaxis and indicate that airway effects of PGF2 alpha are far more complex than previously reported. Moreover, these novel effects suggest that, in addition to its well-known bronchoconstrictor effects, PGF2 alpha directly or indirectly causes airway relaxation, predominantly in large airways.     

Role of nitric oxide in the airway response to exercise in healthy and asthmatic subjects.

A role of nitric oxide (NO) has been suggested in the airway response to exercise. However, it is unclear whether NO may act as a protective or a stimulatory factor. Therefore, we examined the role of NO in the airway response to exercise by using N-monomethyl-L-arginine (L-NMMA, an NO synthase inhibitor), L-arginine (the NO synthase substrate), or placebo as pretreatment to exercise challenge in 12 healthy nonsmoking, nonatopic subjects and 12 nonsmoking, atopic asthmatic patients in a double-blind, crossover study. Fifteen minutes after inhalation of L-NMMA (10 mg), L-arginine (375 mg), or placebo, standardized bicycle ergometry was performed for 6 min using dry air, while ventilation was kept constant. The forced expiratory volume in 1-s response was expressed as area under the time-response curve (AUC) over 30 min. In healthy subjects, there was no significant change in AUC between L-NMMA and placebo treatment [28.6 +/- 17.0 and 1.3 +/- 20.4 (SE) for placebo and L-NMMA, respectively, P = 0.2]. In the asthmatic group, L-NMMA and L-arginine induced significant changes in exhaled NO (P < 0.01) but had no significant effect on AUC compared with placebo (geometric mean +/- SE: -204.3 +/- 1.5, -186.9 +/- 1.4, and -318.1 +/- 1.2%. h for placebo, L-NMMA, and L-arginine, respectively, P > 0.2). However, there was a borderline significant difference in AUC between L-NMMA and L-arginine treatment (P = 0.052). We conclude that modulation of NO synthesis has no effect on the airway response to exercise in healthy subjects but that NO synthesis inhibition slightly attenuates exercise-induced bronchoconstriction compared with NO synthase substrate supplementation in asthma. These data suggest that the net effect of endogenous NO is not inhibitory during exercise-induced bronchoconstriction in asthma.     

Effects of sleep-induced increases in upper airway resistance on ventilation

To determine the effects of the sleep-induced increases in upper airway resistance on ventilatory output, we studied five subjects who were habitual snorers but otherwise normal while awake (AW) and during non-rapid-eye-movement (NREM) sleep under the following conditions: 1) stage 2, low-resistance sleep (LRS); 2) stage 3-4, high-resistance sleep (HRS) (snoring); 3) with continuous positive airway pressure (CPAP); 4) CPAP + end-tidal CO2 partial pressure (PETCO2) mode isocapnic to LRS; and 5) CPAP + PETCO2 isocapnic to HRS. We measured ventilatory output via pneumotachograph in the nasal mask, PETCO2, esophageal pressure, inspiratory and expiratory resistance (RL,I and RL,E). Changes in PETCO2 were confirmed with PCO2 measurements in arterialized venous blood in all conditions in one subject. During wakefulness, pulmonary resistance (RL) remained constant throughout inspiration, whereas in stage 2 and especially in stage 3-4 NREM sleep, RL rose markedly throughout inspiration. Expired minute ventilation (VE) decreased by 12% in HRS, and PETCO2 increased in LRS (3.3 Torr) and HRS (4.9 Torr). CPAP decreased RL,I to AW levels and increased end-expiratory lung volume 0.25-0.93 liter. Tidal volume (VT) and mean inspiratory flow rate (VT/TI) increased significantly with CPAP. Inspiratory time (TI) shortened, and PETCO2 decreased 3.6 Torr but remained 1.3 Torr above AW. During CPAP (RL,I equal to AW), with PETCO2 returned to the level of LRS, VT/TI and VE were 83 and 52% higher than during LRS alone. Also on CPAP, with PETCO2 made equal to HRS, VT, VT/TI, and VE were 67, 112, and 67% higher than during HRS alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood gas changes during and after nonspecific airway challenge in asthmatic and normal subjects

Twenty-eight asymptomatic asthmatics and 28 healthy volunteers were challenged with ultrasonically nebulized distilled water (UNDW). Blood gas composition was monitored transcutaneously (PtCO2 and PtcCO2) over 42 min (20 min for electrode stability, 3 min base line, 5 min during UNDW, and 14 min after UNDW). Flow-volume curves were recorded before and 15 min after UNDW. Forced expiratory volume in 1 s and expiratory flows decreased in asthmatics but not in normal subjects after UNDW. Mean base-line PtCO2 and PtcCO2 were comparable in the two groups. UNDW in normal subjects produced no significant changes in mean PtcCO2 and PtCO2. In asthmatics, the UNDW-induced decrease in mean PtcCO2 was greater and longer lasting, accompanied by a prolonged decrease in mean PtCO2. PtcCO2 and PtCO2 trends showed highly significant differences compared with healthy volunteers (P less than 0.001). Arterial blood gas measurements validated these changes. UNDW in asymptomatic asthmatics gives rise to a greater and more prolonged hyperventilation than in normal subjects and to gas-exchange abnormalities presumably reflecting a ventilation-perfusion mismatching.     

Integrated response of the upper and lower respiratory tract of asthmatic subjects to frigid air.

To evaluate the influence of cold air hyperpnea on integrated upper and lower airway behavior, 22 asthmatic volunteers hyperventilated through their mouths (OHV) and noses (NHV) while pulmonary and nasal function were determined individually and in combination. In the isolated studies, OHV at a minute ventilation of 65 +/- 3 l/min lowered the 1-s forced expiratory volume (FEV(1)) 24 +/- 2% (P < 0. 001) and NHV (40 l/min) induced a 31 +/- 9% (P < 0.001) increase in nasal resistance (NR). In the combined studies, oral hyperpnea reduced the FEV(1) (DeltaFEV(1) 26 +/- 2%, P < 0.001) and evoked a significant rise in NR (DeltaNR 26 +/- 9%, P = 0.01). In contrast, NHV only affected the upper airway. NR rose 33 +/- 9% (P = 0.01), but airway caliber did not change (DeltaFEV(1) 2%, P = 0.27). The results of this investigation demonstrate that increasing the transfer of heat and water in the lower respiratory tract alters bronchial and nasal function in a linked fashion. Forcing the nose to augment its heat-exchanging activity, however, reduces nasal caliber but has no effect on the intrathoracic airways.     

Selected contribution: airway caliber in healthy and asthmatic subjects: effects of bronchial challenge and deep inspirations.

In 9 healthy and 14 asthmatic subjects before and after a standard bronchial challenge and a modified [deep inspiration (DI), inhibited] bronchial challenge and after albuterol, we tracked airway caliber by synthesizing a method to measure airway resistance (Raw; i.e., lung resistance at 8 Hz) in real time. We determined the minimum Raw achievable during a DI to total lung capacity and the subsequent dynamics of Raw after exhalation and resumption of tidal breathing. Results showed that even after a bronchial challenge healthy subjects can dilate airways maximally, and the dilation caused by a single DI takes several breaths to return to baseline. In contrast, at baseline, asthmatic subjects cannot maximally dilate their airways, and this worsens considerably postconstriction. Moreover, after a DI, the dilation that does occur in airway caliber in asthmatic subjects constricts back to baseline much faster (often after a single breath). After albuterol, asthmatic subjects could dilate airways much closer to levels of those of healthy subjects. These data suggest that the asthmatic smooth muscle resides in a stiffer biological state compared with the stimulated healthy smooth muscle, and inhibiting a DI in healthy subjects cannot mimic this.     

Effect of sleep-induced increases in upper airway resistance on respiratory muscle activity

To investigate the response of inspiratory and expiratory muscles to naturally occurring inspiratory resistive loads in the absence of conscious control, five male "snorers" were studied during non-rapid-eye-movement (NREM) sleep with and without continuous positive airway pressure (CPAP). Diaphragm (EMGdi) and scalene (EMGsc) electromyographic activity were monitored with surface electrodes and abdominal EMG activity (EMGab) with wire electrodes. Subjects were studied in the following conditions: 1) awake, 2) stage 2 sleep, 3) stage 3/4 sleep, 4) CPAP during stage 3/4 sleep, 5) CPAP plus end-tidal CO2 pressure (PETCO2) isocapnic to stage 2 sleep, and 6) CPAP plus PETCO2 isocapnic to stage 3/4 sleep. Inspired pulmonary resistance (RL) at peak flow rate and PETCO2 increased in all stages of sleep. Activity of EMGdi, EMGsc, and EMGab increased significantly in stage 3/4 sleep. CPAP reduced RL at peak flow, increased tidal volume and expired ventilation, and reduced PETCO2. EMGdi and EMGsc were reduced, and EMGab was silenced. During CPAP, with CO2 added to make PETCO2 isocapnic to stage 3/4 sleep, EMGsc and EMGab increased, but EMGdi was augmented in only one-half of the trials. EMG activity in this condition, however, was only 75% (EMGsc) and 43% (EMGab) of the activity observed during eupneic breathing in stage 3/4 sleep when PETCO2 was equal but RL was much higher. We conclude that during NREM sleep 1) inspiratory and expiratory muscles respond to internal inspiratory resistive loads and the associated dynamic airway narrowing and turbulent flow developed throughout inspiration, 2) some of the augmentation of respiratory muscle activity is also due to the hypercapnia that accompanies loading, and 3) the abdominal muscles are the most sensitive to load and CO2 and the diaphragm is the least sensitive.     

Correlation between airway responsiveness and proteoglycan production by bronchial fibroblasts from normal and asthmatic subjects

Asthma is characterized by an airway remodeling process involving altered extracellular matrix deposition such as collagen, fibronectin and proteoglycans. Proteoglycans determine tissue mechanical properties and are involved in many important biological aspects. Not surprisingly, it has been suggested that proteoglycan deposition may alter airway properties in asthma including airway hyperresponsiveness. In chronically inflamed airway tissues, fibroblasts likely represent an activated fibrotic phenotype that contributes to the excessive deposition of different extracellular matrix components. To investigate whether this was the case for proteoglycans, the production of hyaluronan, perlecan, versican, small heparan sulphate proteoglycans (HSPGs), decorin and biglycan was quantified in the culture medium of primary bronchial fibroblast cultures, established from four normal and six asthmatic subjects. Values were further correlated to the airway responsiveness (PC(20) methacholine) of donor subjects. Fibroblasts from subjects with the most hyperresponsive airways produced up to four times more total proteoglycans than cells from subjects with less hyperresponsive or normoresponsive airways. We observed a significant negative correlation between the PC(20) and perlecan, small HSPGs and biglycan, while such correlation was absent for decorin and close to significant for hyaluronan and versican. Altered proteoglycan metabolism by bronchial fibroblasts may contribute to the increased proteoglycan deposition in the bronchial mucosa and to airway hyperresponsiveness characterizing asthma.     

Gas exchange during exercise in habitually active asthmatic subjects.

We determined the relations among gas exchange, breathing mechanics, and airway inflammation during moderate- to maximum-intensity exercise in asthmatic subjects. Twenty-one habitually active (48.2 +/- 7.0 ml.kg(-1).min(-1) maximal O2 uptake) mildly to moderately asthmatic subjects (94 +/- 13% predicted forced expiratory volume in 1.0 s) performed treadmill exercise to exhaustion (11.2 +/- 0.15 min) at approximately 90% of maximal O2 uptake. Arterial O2 saturation decreased to < or =94% during the exercise in 8 of 21 subjects, in large part as a result of a decrease in arterial Po2 (PaO2): from 93.0 +/- 7.7 to 79.7 +/- 4.0 Torr. A widened alveolar-to-arterial Po2 difference and the magnitude of the ventilatory response contributed approximately equally to the decrease in PaO2 during exercise. Airflow limitation and airway inflammation at baseline did not correlate with exercise gas exchange, but an exercise-induced increase in sputum histamine levels correlated with exercise Pa(O2) (negatively) and alveolar-to-arterial Po2 difference (positively). Mean pulmonary resistance was high during exercise (3.4 +/- 1.2 cmH2O.l(-1).s) and did not increase throughout exercise. Expiratory flow limitation occurred in 19 of 21 subjects, averaging 43 +/- 35% of tidal volume near end exercise, and end-expiratory lung volume rose progressively to 0.25 +/- 0.47 liter greater than resting end-expiratory lung volume at exhaustion. These mechanical constraints to ventilation contributed to a heterogeneous and frequently insufficient ventilatory response; arterial Pco2 was 30-47 Torr at end exercise. Thus pulmonary gas exchange is impaired during high-intensity exercise in a significant number of habitually active asthmatic subjects because of high airway resistance and, possibly, a deleterious effect of exercise-induced airway inflammation on gas exchange efficiency.     

Adrenergic desensitization in leukocytes of normal and asthmatic subjects.

Cyclic AMP was measured in leukocytes of normal and asthmatic subjects before and after one week of treatment with equal amounts of ephedrine. During the control and placebo periods, the measurements of cyclic AMP in leukocytes of asthmatic subjects were similar to those of normal individuals. After one week of treatment with ephedrine, both groups exhibited suppression of the leukocyte cyclic AMP response to adrenergic stimulation in vitro: however, the suppression of response was significantly greater in asthmatic subjects (p less than .u1). Subcutaneous administration of epinephrine was followed by further suppression of the leukocyte cyclic AMP response to in vitro stimulation which was similar in both groups during all treatment periods. The results indicate that in vivo exposure to adrenergic medications is followed by desensitization of the leukocyte responses to subsequent adrenergic stimulation in vitro. After administration of small doses of medication, the severity and/or duration of desensitization is significantly greater in asthmatic leukocytes.