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.     

Effect of bronchomotor tone on static mechanical properties of lung and ventilation distribution

To study the relationship between bronchomotor tone, static mechanical properties of the lung, and ventilation distribution, we measured the pressure-volume (P-V) curve of the lung and several ventilatory indexes before and after intravenous atropine in eight normal subjects. The indexes of ventilation distribution were derived from multiple breath N2 washouts by a recently developed analysis (7,8). The latter not only provides a sensitive measure of overall ventilation inhomogeneity but distinguishes between the convection-dependent inhomogeneity (CDI) among larger lung units and that due to the interaction of convection and diffusion (DCDI) within the lung periphery. Atropine decreased lung elastic recoil but distensibility, as defined by the exponent (K) in the monoexponential analysis of the P-V data, was unchanged. The overall ventilation inhomogeneity increased by 37% after atropine (P less than 0.02) due to an increase in the CDI component. More importantly, there was a significant correlation between the loss of lung recoil (but not K) and each of the indexes of CDI among the subjects. There was no correlation between the changes in lung recoil and in DCDI. Our findings indicate that normal bronchomotor tone contributes to the elastic recoil of the lung. Furthermore, the tone is distributed in a way that enhances the uniformity of ventilation distribution among diffusion-independent lung units. Presumably this is achieved by minimizing interacinar intrinsic inequalities in static mechanical properties.     

Deep breath reversal and exponential return of methacholine-induced obstruction in asthmatic and nonasthmatic subjects.

A deep breath (DB) during induced obstruction results in a transient reversal with a return to pre-DB levels in both asthmatic and nonasthmatic subjects. The time course of this transient recovery has been reported to be exponential by one group but linear by another group. In the present study, we estimated airway resistance (Raw) from measurements of respiratory system transfer impedance before and after a DB. Nine healthy subjects and nine asthmatic subjects were studied at their maximum response during a methacholine challenge. In all subjects, the DB resulted in a rapid decrease in Raw, which then returned to pre-DB levels. This recovery was well fit with a monoexponential function in both groups, and the time constant was significantly smaller in the asthmatic than the nonasthmatic subjects (11.6 +/- 5.0 and 35.1 +/- 15.9 s, respectively). Obstruction was completely reversed in the nonasthmatic subjects (pre- and postchallenge mean Raw immediately after the DB were 2.03 +/- 0.66 and 2.06 +/- 0.68 cmH2O.l-1.s, respectively), whereas in the asthmatic subjects complete reversal did not occur (2.29 +/- 0.78 and 4.84 +/- 2.64 cmH2O.l-1.s, respectively). Raw after the DB returned to postchallenge, pre-DB values in the nonasthmatic subjects (3.78 +/- 1.56 and 3.97 +/- 1.63 cmH2O.l-1.s, respectively), whereas in the asthmatic subjects it was higher but not significantly so (9.19 +/- 4.95 and 7.14 +/- 3.56 cmH2O.l-1.s, respectively). The monoexponential recovery suggests a first-order process such as airway wall-parenchymal tissue interdependence or renewed constriction of airway smooth muscle.     

Thermoregulatory and respiratory responses in asthmatic and nonasthmatic subjects breathing cold and warm air during exercise in the cold

1.

The effects of whole-body exposure to ambient temperature of −15 °C on thermoregulatory and respiratory responses in asthmatic and nonasthmatic subjects were investigated. The subjects were exposed to inhalation of cold dry and warm humid air during 30 min submaximal exercise.     

Effect of bronchomotor tone on work rate of breathing

We studied the optimal airway caliber for minimizing the work rate of breathing in the lung (W) with different bronchomotor tones in six normal subjects. The inhalation of methacholine contracted airway smooth muscle, and the inhalation of salbutamol relaxed it. To calculate W at a given alveolar ventilation (VA), anatomical dead space (VDanat), pulmonary resistance (RL), and dynamic compliance were measured simultaneously, breath by breath, during various breathing maneuvers. VDanat increased and RL decreased with both increased breathing frequency and tidal volume, even at a given airway tone. This suggests that the airway caliber varied even at a given bronchomotor tone. The minimum W at a given VA increased in constricted airways, but there was no significant difference between control airways after saline inhalation and relaxed airways. It has been suggested that airway smooth muscle tones at both control and relaxed conditions bring W to a minimum and that the airway smooth muscle tone existing in the control state acts to keep the airway caliber optimal in order to minimize the W and stabilize the airway mechanics.     

Effects of vasomotor- and mediator-induced hypotension on bronchomotor tone in swine

We studied the sympathetic neural response on airways to hypotensive stimuli in 19 swine in vivo. The effects of pharmacologically induced hypotension with nitroprusside (NTP) and hypotension elicited by intravenous compound 48/80 (48/80), a mast cell degranulating agent, were compared after equivalent reductions in mean arterial blood pressure (MAP). Reduction of the MAP to 60% of base line with NTP in six swine caused an increase in plasma epinephrine (E) from 60 +/- 28 to 705 +/- 276 pg/ml (P = 0.032) and plasma norepinephrine (NE) from 270 +/- 46 to 796 +/- 131 pg/ml (P = 0.032). Comparable reduction in MAP elicited with 48/80 in six other swine caused a substantially greater increase in both plasma E (9,581 +/- 4,147 pg/ml; P = 0.012 vs. NTP group) and plasma NE (2,239 +/- 637 pg/ml; P = 0.041 vs. NTP group). Catecholamine secretion attenuated mediator-induced changes in lung resistance (RL). In animals receiving 48/80, RL increased from 2.97 +/- 0.31 to 7.44 +/- 0.56 cmH2O.l-1.s. In animals having ganglionic blockade with 7.5 mg/kg iv hexamethonium and beta-adrenergic blockade with propranolol (4.0 mg/kg iv followed by 40 micrograms/kg-1.min-1), comparable doses of 48/80 caused an increase in RL to 18.6 +/- 4.55 cmH2O.l-1.s (P less than 0.04 vs. swine receiving neither hexamethonium nor propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)     

Expression of chemokine receptors by lung T cells from normal and asthmatic subjects

The lung is an important tertiary lymphoid organ with constant trafficking of T cells through the lung in both health and disease. T cell migration is controlled by a combination of adhesion receptors and chemokines expressed on vascular endothelium and in the tissue, often in an organ-specific manner. This leads to selective accumulation of different T cell subsets, a process called lymphocyte homing. There is evidence for a distinct lung-homing pathway, but no specific lung-homing receptors have been described. We analyzed the chemokine receptor profile of lung T cells to determine the extent to which lung T cells shared homing pathways with other organs such as the gut and skin. In addition, we compared expression of receptors in normal and asthmatic individuals to determine whether different pathways were used in health and disease. We observed that lung T cells expressed a profile of chemokine and adhesion receptors distinct from that of gut- and skin-homing T cells although no chemokine receptor specific for the lung was found. In particular, lung T cells expressed CCR5 and CXCR3, but not CCR9 or cutaneous lymphocyte Ag, and only low levels of CCR4 and alpha(4)beta(7). No differences were observed between lung T cells from normal vs asthmatic subjects. This study provides added support for the concept of a lung-homing pathway separate from other mucosal organs such as the gut and suggests that the chemokine pathways that control T cell migration in normal homeostasis and Th2-type inflammatory responses are similar.     

Effects of histamine on bronchial artery blood flow and bronchomotor tone

The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.     

Effect of lung inflation in vivo on airways with smooth muscle tone or edema

Brown, Robert H., Wayne Mitzner, Yonca Bulut, and ElizabethM. Wagner. Effect of lung inflation in vivo on airways with smoothmuscle tone or edema. J. Appl.Physiol. 82(2): 491-499, 1997.Fibrousattachments to the airway wall and a subpleural surrounding pressurecan create an external load against which airway smooth muscle mustcontract. A decrease in this load has been proposed as a possible causeof increased airway narrowing in asthmatic individuals. To study theinteraction between the airways and the surrounding lung parenchyma, weinvestigated the effect of lung inflation on relaxed airways, airwayscontracted with methacholine, and airways made edematous by infusion ofbradykinin into the bronchial artery. Measurements were made inanesthetized sheep by using high-resolution computed tomography tovisualize changes in individual airways. During methacholine infusion,airway area was decreased but increased minimally with increases intranspulmonary pressure. Bradykinin infusion caused a 50% increase inairway wall area and a small decrease in airway luminal area. Incontrast to airways contracted with methacholine, the luminal areaafter bradykinin increased substantially with increases intranspulmonary pressure, reaching 99% of the relaxed area at totallung capacity. Thus airway edema by itself did not prevent fulldistension of the airway at lung volumes approaching total lungcapacity. Therefore, we speculate that if a deep inspiration fails torelieve airway narrowing in vivo, this must be a manifestation ofairway smooth muscle contraction and not airway wall edema.

     

Influence of sleep on lung volume in asthmatic patients and normal subjects

To assess the effect of sleep on functional residual capacity (FRC) in normal subjects and asthmatic patients, 10 adult subjects (5 asthmatic patients with nocturnal worsening, 5 normal controls) were monitored overnight in a horizontal volume-displacement body plethysmograph. With the use of a single inspiratory occlusion technique, we determined that when supine and awake, asthmatic patients were hyperinflated relative to normal controls (FRC = 3.46 +/- 0.18 and 2.95 +/- 0.13 liters, respectively; P less than 0.05). During sleep FRC decreased in both groups, but the decrease was significantly greater in asthmatic patients such that during rapid-eye-movement (REM) sleep FRC was equivalent between the asthmatic and normal groups (FRC = 2.46 +/- 0.23 and 2.45 +/- 0.09 liters, respectively). Specific pulmonary conductance decreased progressively and significantly in the asthmatic patients during the night, falling from 0.047 +/- 0.007 to 0.018 +/- 0.002 cmH2O-1.s-1 (P less than 0.01). There was a significant linear relationship through the night between FRC and pulmonary conductance in only two of the five asthmatic patients (r = 0.55 and 0.65, respectively). We conclude that 1) FRC falls during sleep in both normal subjects and asthmatic patients, 2) the hyperinflation observed in awake asthmatic patients is diminished during non-REM sleep and eliminated during REM sleep, and 3) sleep-associated reductions in FRC may contribute to but do not account for all the nocturnal increase in airflow resistance observed in asthmatic patients with nocturnal worsening.