Airways hyperresponsiveness and the effects of lung inflation.

Lung inflation has a beneficial effect on the airways of healthy subjects. It acts as a bronchoprotector, that is to prevent bronchoconstriction, and as a bronchodilator, in that it reverses bronchial obstruction. The bronchoprotective effect of deep inspiration is more potent than the bronchodilatory one, and the two phenomena appear to advocate different mechanisms. Asthmatics and rhinitics with airways hyperresponsiveness show an impairment in bronchoprotection induced by deep breaths, whereas the bronchodilatory effect, although reduced, is still effective. The lack of the bronchoprotective effect of deep inspiration may contribute to the development of airways hyperresponsiveness. The mechanisms through which lung inflation exerts its beneficial role in healthy subjects, and the factors impairing such an effect in those with airways hyperresponsiveness, are currently under investigation.

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 changing vascular volume on measurement of protein reflection coefficient in ischemic lungs.

In ischemic organs, the protein reflection coefficient (sigma) can be estimated by measuring blood hematocrit (Hct) and protein after increasing static vascular pressure (P(v)). Our original equation for sigma (J Appl Physiol 73: 2616-2622, 1992) assumed a constant vascular volume during convective fluid flux (). In this study, we 1) quantified the rate of vascular volume change (dV/dt) still present in ischemic single ferret lungs after 20 min of P(v) = 30 Torr and 2) developed an equation for sigma that allowed a finite dV/dt. In 25 lungs, we estimated the dV/dt after 20 min at P(v) = 30 Torr by subtracting from the rate of lung weight gain (W(L)). The relationship between (0.15 +/- 0.02 ml/min) and W(L) (0.24 +/- 0.02 g/min) was significant (R = 0.66, P < 0.001), but the slope was <1 (0.41 +/- 0.10, P < 0.05). dV/dt (0.10 +/- 0.02 ml/min) was similar in magnitude to at 20 min. The modified equation for sigma revealed that a finite dV/dt caused the original sigma measurement to underestimate true sigma. A low sigma, high, high baseline Hct, and long filtration time enhanced the error. The error was small, however, and could be minimized by adjusting experimental parameters.

The lack of the bronchoprotective and not the bronchodilatory ability of deep inspiration is associated with airway hyperresponsiveness.

In healthy subjects, deep inspiration (DI) acts both as a bronchodilator and a bronchoprotector. The latter is impaired in asthmatics. We have now evaluated whether the lack of bronchoprotection is related to bronchial hyperresponsiveness (BHR), and whether the bronchodilatory effect is also lost in asthmatics. Ten healthy subjects (PC20 > 75 mg/ml), 12 asthmatics with moderate to severe BHR (PC20 < 1 mg/ml), 14 asthmatics with mild to borderline BHR (1 < PC20 < 25 mg/ml), and 10 rhinitics with mild to borderline BHR (1 < PC20 < 25 mg/ml) underwent single-dose methacholine provocations inducing at least 20% reduction in FEV1 after 20 min of DI inhibition. To measure the bronchodilatory effect, DIs were taken immediately after the postmethacholine spirometry, and lung function was again tested. To measure the bronchoprotective effect, DIs were taken before the administration of spasmogen. All four groups achieved the same reductions in FEV1 and FVC, in the absence of deep breaths (analysis of variance [ANOVA], p = 0.49). Only healthy subjects showed bronchoprotection (percent bronchoprotection, mean +/- SEM; healthy: 79 +/- 4.0; asthmatics with moderate to severe BHR: 12 +/- 14.5; asthmatics with mild to borderline BHR: -7 +/- 19.7; rhinitics with mild to borderline BHR: 2 +/- 14.0). In contrast, DIs were able to partially reverse bronchial obstruction in all four groups, albeit percent bronchodilation in healthy subjects was somewhat stronger. The dissociation between bronchoprotection and bronchodilation suggests that the two effects involve different mechanisms.

Deep inspiration-induced bronchoprotection is stronger than bronchodilation.

We have previously shown that in healthy subjects, deep inspiration (DI) has not only a bronchodilatory but also a bronchoprotective effect that is absent in asthmatic subjects. We conducted the study reported here to test the hypothesis that the bronchoprotective effect is stronger than the bronchodilatory effect, and to determine the extent to which these two effects are related. Ten healthy subjects underwent provocations in which single doses of methacholine, previously shown to reduce FEV(1) by 10% to 20% (Dose 1) and by 20% to 40% (Dose 2) were administered after a 20-min period devoid of DI. To measure the bronchodilator effect, DIs were performed immediately after the first spirometry after methacholine, and were followed by another lung function test. To measure their bronchoprotective effect, DIs were performed before administration of a single dose of methacholine, and the FEV(1) after methacholine was compared with that of another single-dose challenge in which DIs were not included. From these outcomes, bronchodilation and bronchoprotection indices were constructed and compared with each other. At Dose 1 (mild obstruction), the ability of DIs to reverse methacholine-induced obstruction was equal to their ability to prevent it (bronchodilation index [BDI] versus bronchoprotection index [BPI]: 1.62 +/- 0.21 versus 2.02 +/- 0.40 [mean +/- SEM], p = 0.26). At Dose 2, the relative potency of both the bronchodilating and bronchoprotective effects of DIs increased, but bronchoprotection was significantly stronger (BDI versus BPI: 3.40 +/- 0.43 versus 6.98 +/- 1.42, p = 0.02). Correlation analysis of the two indices indicated that as the BPI increased, the BDI reached a plateau. We conclude that in healthy humans, the bronchoprotective effect of lung inflation is stronger than the bronchodilatory effect.

Potent bronchoprotective effect of deep inspiration and its absence in asthma.

In the absence of deep inspirations, healthy individuals develop bronchoconstriction with methacholine inhalation. One hypothesis is that deep inspiration results in bronchodilation. In this study, we tested an alternative hypothesis, that deep inspiration acts as a bronchoprotector. Single-dose methacholine bronchoprovocations were performed after 20 min of deep breath inhibition, in nine healthy subjects and in eight asthmatics, to establish the dose that reduces forced expiratory volume in 1 s by >15%. The provocation was repeated with two and five deep inspirations preceding methacholine. Additional studies were carried out to assess optimization and reproducibility of the protocol and to rule out the possibility that bronchoprotection may result from changes in airway geometry or from differential spasmogen deposition. In healthy subjects, five deep inspirations conferred 85% bronchoprotection. The bronchoprotective effect was reproducible and was not attributable to increased airway caliber or to differential deposition of methacholine. Deep inspirations did not protect the bronchi of asthmatics. We demonstrated that bronchoprotection is a potent physiologic function of lung inflation and established its absence, even in mild asthma. This observation deepens our understanding of airway dysfunction in asthma.

Airway nitric oxide diffusion in asthma: Role in pulmonary function and bronchial responsiveness.

If the nitric oxide (NO) diffusing capacity of the airways (DNO) is the quantity of NO diffusing per unit time into exhaled gas (q) divided by the difference between the concentration of NO in the airway wall (Cw) and lumen, then DNO and C(w) can be estimated from the relationship between exhaled NO concentration and expiratory flow. In 10 normal subjects and 25 asthmatic patients before and after treatment with inhaled beclomethasone, DNO averaged 6.8 +/- 1.2, 25.5 +/- 3.8, and 22.3 +/- 2.7 nl/s/ppb x 10(-3), respectively; C(w) averaged 149 +/- 31.9, 255.3 +/- 46.4, and 108.3 +/- 14.3 ppb, respectively; and DNOC(w) (the maximal from diffusion) averaged 1,020 +/- 157.5, 6,512 +/- 866, and 2,416 +/- 208.5 nl/s x 10(-3), respectively. DNO and DNOC(w) in the asthmatic subjects before and after steroids were greater than in normal subjects (p < 0.0001), but C(w) was not different. Within asthmatic subjects, steroids caused C(w) and DNOC(w) to fall (p < 0.0001), but DNO was unchanged. DNOC(w) after steroids, presumably reflecting maximal diffusion of constitutive NO, was positively correlated with methacholine PC(20) and FEV(1)/FVC before or after steroids. The increased DNO measured in asthmatic patients may reflect upregulation of nonadrenergic, noncholinergic, NO-producing nerves in airways in compensation for decreased sensitivity of airway smooth muscle to the relaxant effects of endogenous NO.

Airway narrowing in healthy humans inhaling methacholine without deep inspirations demonstrated by HRCT.

Normal subjects prevented from taking a deep breath show changes in airflow similar to those of asthmatics when challenged with methacholine (MCh). To confirm airway narrowing by MCh in this setting and to determine its location, we concurrently measured changes in airway lumenal area using high resolution computed tomography (HRCT) and airflow using partial spirometry in five normal subjects challenged with increasing doses of MCh under prohibition of deep breaths. In an attempt to improve imaging accuracy, we corrected for the changes in lung volume during bronchoprovocation. At every step of the provocation, scanning was performed at approximately the same lung volume. On the HRCT images, airway area decreased in response to the increasing doses of MCh to 91 +/- 2%, 88 +/- 2%, and 80 +/- 2% of baseline at the doses of MCh 0.25, 0.75, and 2.5 mg/ml, respectively (p < 0.001). Airway narrowing showed no predilection for particular airway sizes and occurred in a heterogeneous pattern. The changes in the mean airway lumenal area as measured by HRCT and the mean partial spirometric outcomes were highly correlated: FEV(1)p (r(2) = 0.46, p = 0.001), FVCp (r(2) = 0.20, p = 0.05), FEV(1)/FVCp (r(2) = 0.55, p = 0.002), MMEFp (r(2) = 0.31, p = 0.01), and taup (r(2) = 0.51, p = 0.0004). We conclude that in normal subjects who are prevented from taking a deep breath, the spirometric changes occurring with aerosol MCh challenge are associated with conducting airway narrowing.

Effect of ventilation on vascular permeability and cyclic nucleotide concentrations in ischemic sheep lungs.

Ventilation during ischemia attenuates ischemia-reperfusion lung injury, but the mechanism is unknown. Increasing tissue cyclic nucleotide levels has been shown to attenuate lung ischemia-reperfusion injury. We hypothesized that ventilation prevented increased pulmonary vascular permeability during ischemia by increasing lung cyclic nucleotide concentrations. To test this hypothesis, we measured vascular permeability and cGMP and cAMP concentrations in ischemic (75 min) sheep lungs that were ventilated (12 ml/kg tidal volume) or statically inflated with the same positive end-expiratory pressure (5 Torr). The reflection coefficient for albumin (sigmaalb) was 0.54 +/- 0.07 and 0.74 +/- 0. 02 (SE) in nonventilated and ventilated lungs, respectively (n = 5, P < 0.05). Filtration coefficients and capillary blood gas tensions were not different. The effect of ventilation was not mediated by cyclic compression of alveolar capillaries, because negative-pressure ventilation (n = 4) also was protective (sigmaalb = 0.78 +/- 0.09). The final cGMP concentration was less in nonventilated than in ventilated lungs (0.02 +/- 0.02 and 0.49 +/- 0. 18 nmol/g blood-free dry wt, respectively, n = 5, P < 0.05). cAMP concentrations were not different between groups or over time. Sodium nitroprusside increased cGMP (1.97 +/- 0.35 nmol/g blood-free dry wt) and sigmaalb (0.81 +/- 0.09) in nonventilated lungs (n = 5, P < 0.05). Isoproterenol increased cAMP in nonventilated lungs (n = 4, P < 0.05) but had no effect on sigmaalb. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester had no effect on lung cGMP (n = 9) or sigmaalb (n = 16) in ventilated lungs but did increase pulmonary vascular resistance threefold (P < 0.05) in perfused sheep lungs (n = 3). These results suggest that ventilation during ischemia prevented an increase in pulmonary vascular protein permeability, possibly through maintenance of lung cGMP by a nitric oxide-independent mechanism.

Rapid reversibility of the allergen-induced pulmonary late-phase reaction by an intravenous beta2-agonist.

This study was performed to determine the degree to which beta2-adrenergic receptor agonists can reverse the allergen-induced late reduction in lung function. On two occasions, seven asthmatic subjects were administered terbutaline or its vehicle by intravenous infusion 7 h after inhaled allergen, at which point the forced expiratory volume in 1 s was 57% of baseline. On another occasion, terbutaline was infused at baseline to determine maximal attainable bronchodilation. After allergen challenge, terbutaline rapidly improved lung function. At the end of terbutaline infusion, the forced expiratory volume in 1 s reached 100 +/- 1.3% of baseline and 84.2 +/- 4.3% of maximal attainable value, but the bronchodilating effect of the beta-agonist did not plateau. The values for forced vital capacity were 102 +/- 1.3% of baseline and 95.1 +/- 3% of maximal attainable value. The kinetics of the terbutaline effect, when it was infused at baseline, were similar to those in the late phase. Because the late-phase reduction in lung function is rapidly reversible by beta2-adrenergic agonists, we conclude that it is caused mainly by bronchial smooth muscle spasm.

Lung volume reduction surgery and airflow limitation.

Interest has recently been renewed in lung volume reduction surgery (LVRS) for end-stage emphysema. However, numerous questions about its role in the treatment of emphysema remain, including the clinical characteristics of optimal candidates and its mechanism of improvement in pulmonary function. In this report, we develop a mathematical analysis and graphic depiction of the mechanism of improvement in expiratory airflow and vital capacity. This analysis is based on consideration of the interaction between lung function and respiratory muscle function. We also reexamine previously published pulmonary mechanics in patients with alpha1-antitrypsin deficiency, chronic obstructive pulmonary disease, and asthma. We find a major determinant of airflow limitation common to these diseases is the ratio of residual volume to total lung capacity (RV/TLC). Moreover, RV/TLC is found to be the single most important determinant of the improvement in pulmonary function after LVRS. Regardless of the specific underlying lung disease, the impairment of airflow is due primarily to mismatch between the sizes of the lung and the chest wall, and the effects of LVRS are almost exclusively due to improvement of that match. This analysis can be used to develop testable hypotheses to guide patient selection for this procedure.

Direct assessment of small airways reactivity in human subjects.

Our knowledge of airways reactivity to inflammatory agonists is derived predominantly from tests dominated by large airway responsiveness. To determine directly, the histamine responsiveness of the smallest airways, eight normal and 11 asymptomatic asthmatic subjects were studied utilizing a wedged bronchoscope technique. A fiberoptic bronchoscope was wedged in the anterior segment of the right upper lobe and a double-lumen catheter was advanced through the working channel to its tip. With a constant flow of gas (5% CO2 in air) through one lumen of the catheter, pressure at the tip of the bronchoscope was measured with the subject breath-holding at FRC. Peripheral airways resistance (Rp) was measured at baseline and after saline, histamine (10, 50, 100 mg/ml) and isoproterenol (2 mg/ml) challenge through the bronchoscope. Baseline Rp of asthmatics (0.041 +/- 0.015 cm H2O/ml/min; mean +/- SE) was significantly greater than normal subjects (0.011 +/- 0.003 cm H2O/ml/min; p = 0.019). The log of the concentration of histamine that caused a 100% increase in peripheral airways response was greater in the normal subjects than in the asthmatic subjects (p = 0.0114) and correlated with whole lung responsiveness to histamine in asthmatics (r = 0.847, p < 0.05). Isoproterenol reversed completely the increase in Rp in normal subjects but not asthmatic subjects. The results of this study demonstrate that the resistance of the smallest peripheral airways, when measured directly, increased when challenged locally with histamine in both normal subjects and asthmatic subjects. However, the peripheral airways responsiveness was significantly enhanced in asthmatic subjects relative to normal controls.

Assessment of protein permeability in normal human systemic circulation.

Vascular permeability to oncotic agents is an important determinant of transvascular fluid flux (J) and systemic fluid balance. In this study, a technique was developed to measure protein reflection coefficients (omega) for albumin (Alb), immunoglobulin (Ig) G, and IgM in the intact human systemic circulation to evaluate the role of vascular protein permeability in health and disease. A mathematical model was developed to calculate omega in the forearm circulation from changes in venous hematocrit and protein concentration that occur during edema formation. Assumptions required for the model were validated in an initial set of experiments in normal subjects when edema was induced by inflating a pneumatic cuff on the upper arm. A second series of experiments assessed omega for Alb, IgG, and IgM in men (n = 7) and in women in the follicular (n = 5) and luteal (n = 4) phases of the menstrual cycle. There was an increasing trend in omega with molecular size in aggregated subjects [omega Alb = 0.81 +/- 0.12 (SE), omega IgG = 0.88 +/- 0.12, omega IgM = 0.92 +/- 0.18; P = 0.088]. These values were consistent with those obtained with in vitro preparations. omega values were lower in women in the luteal than in the follicular phase (P = 0.047). We conclude that the assumptions required for this model can be achieved in the intact forearm circulation and that there are menstrual phase-related differences in vascular protein permeability in normal women.

Structural basis for alterations in upper airway collapsibility.

To determine the structural basis for alterations in upper airway (UA) collapsibility, the pharyngeal critical pressure (Pcrit) was measured in an isolated feline upper airway preparation. The effect of airway elongation and dilation was explored by displacing the trachea caudally and the tongue anteriorly, respectively. With caudal-tracheal displacement, Pcrit fell progressively, a result that can be attributed to increased tension within the pharyngeal mucosa. In contrast, anterior-tongue displacement decreased Pcrit when the trachea had been caudally displaced but not with the trachea in the neutral position. These findings suggest that longitudinal tension within the airway mucosa modulates both Pcrit and the response in Pcrit to dilating forces. A mechanical model to account for these findings is discussed.

Effect of tracheal and tongue displacement on upper airway airflow dynamics.

We have previously shown that caudal tracheal displacement alters the airflow dynamics of the upper airway. In the present study, we specifically examined the effects of tongue and tracheal displacement on upper airway airflow dynamics. To determine how tongue and tracheal displacement modulate maximal inspiratory airflow (VImax), we analyzed the pressure-flow relationships obtained in the isolated upper airway of paralyzed cats. VImax and its determinants, the pharyngeal critical pressure (Pcrit) and the nasal resistance (Rn) upstream to the flow-limiting site, were measured as tongue displacement and tracheal displacement were systematically varied. Four results were obtained: 1) there was no independent effect of tongue displacement on VImax, Pcrit, or Rn; 2) there was an increase in VImax with 2 cm of tracheal displacement, which was associated with a decrease in Pcrit and an increase in Rn; 3) there was an interactive effect of tongue and tracheal displacement on VImax and Pcrit but not on Rn; and 4) there was a large increase in VImax with tongue displacement > 2.5 cm with the trachea nondisplaced, which was associated with a large decrease in Pcrit and a large increase in Rn. We conclude that tongue and tracheal displacement exert differing influences on airflow dynamics and present a mechanical model of the upper airway that explains these results.

Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration.

We hypothesized that hyperresponsiveness in asthma is caused by an impairment in the ability of inspiration to stretch airway smooth muscle. If the hypothesis was correct, we reasoned that the sensitivity to inhaled methacholine in normal and asthmatic subjects should be the same if the challenge was carried out under conditions where deep inspirations were prohibited. 10 asthmatic and 10 normal subjects received increasing concentrations of inhaled methacholine under conditions where forced expirations from a normal end-tidal inspiration were performed. When no deep inspirations were allowed, the response to methacholine was similar in the normal and asthmatic subjects, compatible with the hypothesis we propose. Completely contrary to our expectations, however, was the marked responsivity to methacholine that remained in the normal subjects after deep breaths were initiated. 6 of the 10 normal subjects had > 20% reduction in forced expiratory volume in one second (FEV 1) at doses of methacholine < 8 mg/ml, whereas there was < 15% reduction with 75 mg/ml during routine challenge. The ability of normal subjects to develop asthmatic responses when the modulating effects of increases in lung volume was voluntarily suppressed suggests that an intrinsic impairment of the ability of inspiration to stretch airway smooth muscle is a major feature of asthma.

CPAP reduces inspiratory work more than dyspnea during hyperinflation with intrinsic PEEP.

Hyperinflation with intrinsic positive end-expiratory pressure (PEEPi) loads the respiratory muscles and causes dyspnea in obstructive lung disease. Continuous positive airway pressure (CPAP) has shown some efficacy in reducing inspiratory work and dyspnea. However, in obstructive lung disease, inspiratory work and dyspnea may be increased by additional factors that may not be affected by CPAP. Therefore, to study the effects of hyperinflation with intrinsic PEEP and CPAP in isolation, we used a mechanical analog of airway closure to increase end-expiratory lung volume in normal subjects. In five subjects in whom inspiratory work was measured, increasing end-expiratory lung volume by 1 and 2 L increased inspiratory work per breath from 0.42 +/- 0.04 J to 1.17 +/- 0.15 J (p < 0.05 compared with baseline) and 1.58 +/- 0.22 J (p < 0.05 compared with baseline and to the lesser level of hyperinflation). Although CPAP reduced work per breath and per minute to levels not significantly different from baseline, it had little effect on dyspnea. In ten subjects hyperinflated to 2.4 +/- 0.12 L above FRC, breathing could be sustained 19.5 +/- 4.5 min before quitting the load. This was increased to 26.7 +/- 5.2 min by 10 cm H2O CPAP (p = 0.052). Inspiratory dyspnea was modestly reduced by CPAP during these endurance trials. We conclude that CPAP can substantially ameliorate the respiratory work load induced by hyperinflation with intrinsic PEEP. However, the effects of CPAP on dyspnea and endurance are more limited. This suggests that the limits to breathing at high lung volumes are related to factors in addition to respiratory muscle work, and that CPAP may be of more value in reducing the work than in relieving the distress of obstructive lung disease.