Airway responsiveness to methacholine: effects of deep inhalations and airway inflammation.

We determined the dose-response curves to inhaled methacholine (MCh) in 16 asthmatic and 8 healthy subjects with prohibition of deep inhalations (DIs) and with 5 DIs taken after each MCh dose. Flow was measured on partial expiratory flow-volume curves at an absolute lung volume (plethysmographically determined) equal to 25% of control forced vital capacity (FVC). Airway inflammation was assessed in asthmatic subjects by analysis of induced sputum. Even when DIs were prohibited, the dose of MCh causing a 50% decrease in forced partial flow at 25% of control FVC (PD(50)MCh) was lower in asthmatic than in healthy subjects (P < 0.0001). In healthy but not in asthmatic subjects, repeated DIs significantly decreased the maximum response to MCh [from 90 +/- 4 to 62 +/- 8 (SD) % of control, P < 0.001], increased PD(50)MCh (P < 0.005), without affecting the dose causing 50% of maximal response. In asthmatic subjects, neither PD(50)MCh when DIs were prohibited nor changes in PD(50)MCh induced by DIs were significantly correlated with inflammatory cell numbers or percentages in sputum. We conclude that 1) even when DIs are prohibited, the responsiveness to MCh is greater in asthmatic than in healthy subjects; 2) repeated DIs reduce airway responsiveness in healthy but not in asthmatic subjects; and 3) neither airway hyperresponsiveness nor the inability of DIs to relax constricted airways in asthmatic subjects is related to the presence of inflammatory cells in the airways.     

Mechanisms for isolated volume response to a bronchodilator in patients with COPD.

We hypothesized that an altered effect of lung inflation on airway caliber may in part explain the isolated volume response to bronchodilators, i.e., an increase of forced vital capacity (FVC) without change in 1-s forced expiratory volume (FEV(1)). Small-airway caliber was measured by high-resolution computed tomography at functional residual capacity and total lung capacity in five chronic obstructive pulmonary disease patients with an isolated increase of FVC (FVC responders) and five with an increase of both FVC and FEV(1) (FVC-FEV(1) responders) after inhalation of salbutamol. In FVC-FEV(1) responders, the airway diameter increased with the cube root of increase in lung volume but was unchanged or even decreased in four of five FVC responders. FVC responders had more severe emphysema, as inferred from lung function and imaging studies, than FVC-FEV(1) responders. We speculate that longitudinal traction or space competition (Verbeken EK, Cauberghs M, and Van de Woestijne KP, J Appl Physiol 81: 2468-2480, 1996) are possible underlying mechanisms. We conclude that the isolated volume response to bronchodilators is associated with severe emphysema and likely results from an altered effect of lung inflation on airway caliber.     

Lung elastic recoil during breathing at increased lung volume.

During dynamic hyperinflation with induced bronchoconstriction, there is a reduction in lung elastic recoil at constant lung volume (R. Pellegrino, O. Wilson, G. Jenouri, and J. R. Rodarte. J. Appl. Physiol. 81: 964-975, 1996). In the present study, lung elastic recoil at control end inspiration was measured in normal subjects in a volume displacement plethysmograph before and after voluntary increases in mean lung volume, which were achieved by one tidal volume increase in functional residual capacity (FRC) with constant tidal volume and by doubling tidal volume with constant FRC. Lung elastic recoil at control end inspiration was significantly decreased by approximately 10% within four breaths of increasing FRC. When tidal volume was doubled, the decrease in computed lung recoil at control end inspiration was not significant. Because voluntary increases of lung volume should not produce airway closure, we conclude that stress relaxation was responsible for the decrease in lung recoil.     

Effects of exercise and beta 2-agonists on lung function in chronic obstructive pulmonary disease.

The effects of inhaled bronchodilators at rest and during exercise were studied in 15 subjects with chronic obstructive pulmonary disease. In a crossover study against placebo, albuterol caused a significant increase in expiratory flow and reduced lung hyperinflation and dyspnea at rest, but this was not associated with differences in symptoms with exercise or any relevant parameter of physical performance. Dynamic hyperinflation occurred during exercise similarly after placebo or albuterol and was associated with a reduction of forced expiratory flows. This, in turn, was correlated with the bronchoconstrictor effect of deep inhalation determined at rest. In a parallel group study, expiratory flow was increased by 3-wk treatment with salmeterol (n = 9) but not with placebo (n = 6). However, in neither group was the response to exercise different from baseline. These results suggest that in chronic obstructive pulmonary disease effective pharmacological bronchodilation at rest may not be predictive of benefits of exercise tolerance. This may be related to the occurrence of airway narrowing during exercise, particularly when a deep inhalation at rest is followed by a decrease in expiratory flow.     

Respiratory dynamics during laughter.

Lung and chest wall mechanics were studied during fits of laughter in 11 normal subjects. Laughing was naturally induced by showing clips of the funniest scenes from a movie by Roberto Benigni. Chest wall volume was measured by using a three-dimensional optoelectronic plethysmography and was partitioned into upper thorax, lower thorax, and abdominal compartments. Esophageal (Pes) and gastric (Pga) pressures were measured in seven subjects. All fits of laughter were characterized by a sudden occurrence of repetitive expiratory efforts at an average frequency of 4.6 +/- 1.1 Hz, which led to a final drop in functional residual capacity (FRC) by 1.55 +/- 0.40 liter (P < 0.001). All compartments similarly contributed to the decrease of lung volumes. The average duration of the fits of laughter was 3.7 +/- 2.2 s. Most of the events were associated with sudden increase in Pes well beyond the critical pressure necessary to generate maximum expiratory flow at a given lung volume. Pga increased more than Pes at the end of the expiratory efforts by an average of 27 +/- 7 cmH2O. Transdiaphragmatic pressure (Pdi) at FRC and at 10% and 20% control forced vital capacity below FRC was significantly higher than Pdi at the same absolute lung volumes during a relaxed maneuver at rest (P < 0.001). We conclude that fits of laughter consistently lead to sudden and substantial decrease in lung volume in all respiratory compartments and remarkable dynamic compression of the airways. Further mechanical stress would have applied to all the organs located in the thoracic cavity if the diaphragm had not actively prevented part of the increase in abdominal pressure from being transmitted to the chest wall cavity.     

G(s) protein dysfunction in allergen-challenged human isolated passively sensitized bronchi

We studied the intracellular mechanisms of allergen-induced beta(2)-adrenoceptor dysfunction in human isolated passively sensitized bronchi. Sensitization was obtained by overnight incubation of bronchial rings with serum containing a high specific IgE level to Dermatophagoides but a low total IgE level. Allergen challenge was done by incubation with a Dermatophagoides mix. The G(s) protein stimulant cholera toxin (2 microg/ml) displaced the carbachol (CCh) concentration-response curves of control and sensitized but not of challenged rings to the right. Cholera toxin (10 microg/ml) displaced the concentration-response curves to CCh of control, sensitized, and challenged rings to the right, but this effect was less in challenged rings. The effects of the G(i) protein inhibitor pertussis toxin (250 ng/ml or 1 microg/ml) on salbutamol concentration-relaxation curves did not differ significantly between challenged and sensitized rings. The adenylyl cyclase activator forskolin and the Ca(2+)-activated K(+)-channel opener NS-1619 relaxed CCh-contracted bronchial rings without significant differences between control, sensitized, and challenged rings. Neither G(i) nor G(s) alpha-subunit expression differed between control, sensitized, and challenged tissues. We conclude that G(s) protein dysfunction may be a mechanism of allergen-induced beta(2)-adrenoceptor dysfunction in human isolated passively sensitized bronchi.