Partitioning of lung tissue response and inhomogeneous airway constriction at the airway opening

Suki, Béla, Huichin Yuan, Qin Zhang, and Kenneth R. Lutchen. Partitioning of lung tissue response and inhomogeneous airway constriction at the airway opening. J. Appl.Physiol. 82(4): 1349-1359, 1997.During abronchial challenge, much of the observed response of lung tissues isan artifactual consequence of inhomogeneous airway constriction.Inhomogeneities, in the sense of time constant inequalities, are aninherently linear phenomenon. Conversely, if lung tissues respond to abronchoagonist, they become more nonlinear. On the basis of thesedistinct responses, we present an approach to separate real tissuechanges from airway inhomogeneities. We developed a lung model thatincludes airway inhomogeneities in the form of a continuousdistribution of airway resistances and nonlinear viscoelastic tissues.Because time domain data are dominated by nonlinearities, whereasfrequency domain data are most sensitive to inhomogeneities, we apply acombined time-frequency domain identification scheme. This model wastested with simulated data from a morphometrically based airway modelmimicking gross peripheral airway inhomogeneities and shown capable ofrecovering all tissue parameters to within 15% error. Application toour previously measured data suggests that in dogs during histamine infusion 1) the distribution ofairway resistances increases widely and2) lung tissues do respond but lessso than previously reported. This approach, then, is unique in itsability to differentiate between airway and tissue responses to anagonist from a single broadband measurement made at the airway opening.

     

Halothane decreases both tissue and airway resistances in excised canine lungs

Studies of the anesthetic effects on the airway often use pulmonary resistance (RL) as an index of airway caliber. To determine the effects of the volatile anesthetic, halothane, on tissue and airway components of RL, we measured both components in excised canine lungs before and during halothane administration. Tissue resistance (Rti), airway resistance (Raw), and dynamic lung compliance (CL, dyn) were determined at constant tidal volume and at ventilatory frequencies ranging from 5 to 45 min-1 by an alveolar capsule technique. Halothane decreased RL at each breathing frequency by causing significant decreases in both Raw and Rti but did not change the relative contribution of Rti to RL at any frequency. Halothane increased CL,dyn at each breathing frequency, although there was little change in the static pressure-volume relationship. The administration of isoproterenol both airway and tissue components of RL; it may act by relaxing the contractile elements in the lung. Both components must be considered when the effects of volatile anesthetics on RL are interpreted.     

Determination of airway and tissue resistances after antigen and methacholine in nonhuman primates

Madwed, Jeffrey B., and Andrew C. Jackson.Determination of airway and tissue resistances after antigen andmethacholine in nonhuman primates. J. Appl.Physiol. 83(5): 1690-1696, 1997.Antigen challenge of Ascaris suum-sensitiveanimals has been used as a model of asthma in humans. However, noreports have separated total respiratory resistance into airway (Raw)and tissue (Rti) components. We compared input impedance (Zin) andtransfer impedance (Ztr) to determine Raw and Rti in anesthetizedcynomolgus monkeys under control and bronchoconstricted conditions. Zindata between 1 and 64 Hz are frequency dependent during baselineconditions, and this frequency dependence shifts in response toA. suum or methacholine. Thus itcannot be modeled with the DuBois model, and estimates of Raw and Rticannot be determined. With Ztr, baseline data were much less variablethan Zin in all monkeys. After bronchial challenge withA. suum or methacholine, the absoluteamplitude of the resistive component of Ztr increased and its zerocrossing shifted to higher frequencies. These data can estimate Raw and Rti with the six-element DuBois model. Therefore, in monkeys, Ztr hasadvantages over other measures of lung function, since it provides amethodology to separate estimates of Raw and Rti. In conclusion, Ztrshows spectral features similar to those reported in healthy andasthmatic humans.

     

Effects of lung volume on maximal methacholine-induced bronchoconstriction in normal humans

We examined the effects of lung volume on the bronchoconstriction induced by inhaled aerosolized methacholine (MCh) in seven normal subjects. We constructed dose-response curves to MCh, using measurements of inspiratory pulmonary resistance (RL) during tidal breathing at functional residual capacity (FRC) and after a change in end-expiratory lung volume (EEV) to either FRC -0.5 liter (n = 5) or FRC +0.5 liter (n = 2). Aerosols of MCh were generated using a nebulizer with an output of 0.12 ml/min and administered for 2 min in progressively doubling concentrations from 1 to 256 mg/ml. After MCh, RL rose from a base-line value of 2.1 +/- 0.3 cmH2O. 1-1 X s (mean +/- SE; n = 7) to a maximum of 13.9 +/- 1.8. In five of the seven subjects a plateau response to MCh was obtained at FRC. There was no correlation between the concentration of MCh required to double RL and the maximum value of RL. The dose-response relationship to MCh was markedly altered by changing lung volume. The bronchoconstrictor response was enhanced at FRC - 0.5 liter; RL reached a maximum of 39.0 +/- 4.0 cmH2O X 1-1 X s. Conversely, at FRC + 0.5 liter the maximum value of RL was reduced in both subjects from 8.2 and 16.6 to 6.0 and 7.7 cmH2O X 1-1 X s, respectively. We conclude that lung volume is a major determinant of the bronchoconstrictor response to MCh in normal subjects. We suggest that changes in lung volume act to alter the forces of interdependence between airways and parenchyma that oppose airway smooth muscle contraction.     

Cold-induced bronchoconstriction: role of cutaneous reflexes vs. direct airway effects

To determine the relative contributions of direct airway vs. reflex cutaneous thermal receptor stimulation in cold-induced bronchoconstriction, we isolated these two aspects of cold exposure in 10 asthmatics and 13 normal subjects. Ice packs were applied to the skin of the face, chest, thigh, and upper arm in random sequence while serially measuring specific conductance. In this fashion a limited mapping of skin-mediated bronchoconstriction was established. Warm packs were applied to the same areas of control for any potential nonspecific stimulatory effects. Cooling the skin induced bronchoconstriction to a similar degree in both groups; this effect was very small, did not induce symptoms, and was only seen with stimulation of the face. At another time, the subjects performed isocapnic hyperventilation of frigid air to ascertain their response to direct airway cooling. A moderate but significant correlation existed between skin and airway sensitivity; however, the magnitude of the two responses differed markedly. Breathing cold air at rest had no effect on lung function; however, elevating ventilation promptly produced bronchial narrowing. Hence, in a cold environment, the most potent stimulus for the development of airway obstruction in asthmatics derives from a direct airway effect.     

Partitioning of airway and respiratory tissue mechanical impedances by body plethysmography

Peslin, R., and C. Duvivier. Partitioning of airway andrespiratory tissue mechanical impedances by body plethysmography. J. Appl. Physiol. 84(2): 553-561, 1998.We have tested the feasibility of separating the airway (Zaw)and tissue (Zti) components of total respiratory input impedance(Zrs,in) in healthy subjects by measuring alveolar gas compression bybody plethysmography (Vpl) during pressure oscillations at the airwayopening. The forced oscillation setup was placed inside a bodyplethysmograph, and the subjects rebreathedBTPS gas. Zrs,in and the relationship between Vpl and airway flow (Hpl) were measured from 4 to 29 Hz. Zawand Zti were computed from Zrs,in and Hpl by using the monoalveolar T-network model and alveolar gas compliance derived from thoracic gasvolume. The data were in good agreement with previous observations: airway and tissue resistance exhibited some positive and negative frequency dependences, respectively; airway reactance was consistent with an inertance of 0.015 ± 0.003 hPa · s² · l¹and tissue reactance with an elastance of 36 ± 8 hPa/l. The changes seen with varying lung volume, during elastic loading of the chest andduring bronchoconstriction, were mostly in agreement with the expectedeffects. The data, as well as computer simulation, suggest that thepartitioning is unaffected by mechanical inhomogeneity and onlymoderately affected by airway wall shunting.

     

Methacholine-induced bronchoconstriction in dogs: effects of lung volume and O3 exposure

The maximal effect induced by methacholine (MCh) aerosols on pulmonary resistance (RL), and the effects of altering lung volume and O3 exposure on these induced changes in RL, was studied in five anesthetized and paralyzed dogs. RL was measured at functional residual capacity (FRC), and lung volumes above and below FRC, after exposure to MCh aerosols generated from solutions of 0.1-300 mg MCh/ml. The relative site of response was examined by magnifying parenchymal [RL with large tidal volume (VT) at fast frequency (RLLS)] or airway effects [RL with small VT at fast frequency (RLSF)]. Measurements were performed on dogs before and after 2 h of exposure to 3 ppm O3. MCh concentration-response curves for both RLLS and RLSF were sigmoid shaped. Alterations in mean lung volume did not alter RLLS; however, RLSF was larger below FRC than at higher lung volumes. Although O3 exposure resulted in small leftward shifts of the concentration-response curve for RLLS, the airway dominated index of RL (RLSF) was not altered by O3 exposure, nor was the maximal response using either index of RL. These data suggest O3 exposure does not affect MCh responses in conducting airways; rather, it affects responses of peripheral contractile elements to MCh, without changing their maximal response.     

Effects of lung volume, bronchoconstriction, and cigarette smoke on morphometric airway dimensions

To examine the role of airway wall thickening in the bronchial hyperresponsiveness observed after exposure to cigarette smoke, we compared the airway dimensions of guinea pigs exposed to smoke (n = 7) or air (n = 7). After exposure the animals were anesthetized with urethan, pulmonary resistance was measured, and the lungs were removed, distended with Formalin, and fixed near functional residual capacity. The effects of lung inflation and bronchoconstriction on airway dimensions were studied separately by distending and fixing lungs with Formalin at total lung capacity (TLC) (n = 3), 50% TLC (n = 3), and 25% TLC (n = 3) or near residual volume after bronchoconstriction (n = 3). On transverse sections of extraparenchymal and intraparenchymal airways the following dimensions were measured: the internal area (Ai) and internal perimeter (Pi), defined by the epithelium, and the external area (Ae) and external perimeter (Pe), defined by the outer border of smooth muscle. Airway wall area (WA) was then calculated, WA = Ae - Ai. Ai, Pe, and Ae decreased with decreasing lung volume and after bronchoconstriction. However, WA and Pi did not change significantly with lung volume or after bronchoconstriction. After cigarette smoke exposure airway resistance was increased (P less than 0.05); however, there was no difference in WA between the smoke- and air-exposed groups when the airways were matched by Pi. We conclude that Pi and WA are constant despite changes in lung volume and smooth muscle tone and that airway hyperresponsiveness induced by cigarette smoke is not mediated by increased airway wall thickness.     

Partitioning of respiratory mechanics in halothane-anesthetized humans

In five spontaneously breathing anesthetized subjects [halothane approximately 1 minimal alveolar concentration (MAC), 70% N2O, 30% O2], flow, changes in lung volume, and esophageal and airway opening pressure were measured in order to partition the elastance (Ers) and flow resistance (Rrs) of the total respiratory system into the lung and chest wall components. Ers averaged (+/- SD) 23.0 +/- 4.9 cmH2O X l-1, while the corresponding values of pulmonary (EL) and chest wall (EW) elastance were 14.3 +/- 3.2 and 8.7 +/- 3.0 cmH2O X l-1, respectively. Intrinsic Rrs (upper airways excluded) averaged 2.3 +/- 0.2 cmH2O X l-1 X s, the corresponding values for pulmonary (RL) and chest wall (RW) flow resistance amounting to 0.8 +/- 0.4 and 1.5 +/- 0.5 cmH2O X l-1 X s, respectively. Ers increased relative to normal values in awake state, mainly reflecting increased EL. Rw was higher than previous estimates on awake seated subjects (approximately 1.0 cmH2O X l-1 X s). RL was relatively low, reflecting the fact that the subjects had received atropine (0.3-0.6 mg) and were breathing N2O. This is the first study in which both respiratory elastic and flow-resistive properties have been partitioned into lung and chest wall components in anesthetized humans.     

Upper airway resistances in fetal sheep: the influence of breathing activity

Fetal breathing movements (FBM) and lung liquid volume are known to affect lung development, but little is known about mechanisms controlling movement of liquid through the upper respiratory tract (URT). Therefore we measured resistances of the URT in 8 unanesthetized fetal sheep during late gestation while FBM were monitored from pressures in the lower trachea or from electromyogram of respiratory muscles. URT resistance to liquid flow toward the amniotic sac increased from 3.5 +/- 1.9 Torr X ml-1 X min during episodes of FBM to 21.1 +/- 5.7 Torr X ml-1 X min during apnea. Laryngeal resistance during apnea was greater (P less than 0.001) than supralaryngeal resistance in each of six fetuses in which URT resistance was partitioned. Fetal paralysis abolished the increase in laryngeal resistance to efflux that was previously related to the high-voltage electrocortical state and apnea. We were unable to quantify URT resistance to fluid movement toward the lungs because the larynx acted as a valve, permitting flow toward the lungs only in the presence of FBM. The supralaryngeal portion of the URT also apparently acts as a valve, normally preventing the entry of amniotic fluid into the pharynx. These findings help to explain our earlier observations that efflux of liquid from the fetal lungs is greater during episodes of FBM than during apnea.     

Effects of rapid saline infusion on lung mechanics and airway responsiveness in humans.

Lung mechanics and airway responsiveness to methacholine (MCh) were studied in seven volunteers before and after a 20-min intravenous infusion of saline. Data were compared with those of a time point-matched control study. The following parameters were measured: 1-s forced expiratory volume, forced vital capacity, flows at 40% of control forced vital capacity on maximal (Vm(40)) and partial (Vp(40)) forced expiratory maneuvers, lung volumes, lung elastic recoil, lung resistance (Rl), dynamic elastance (Edyn), and within-breath resistance of respiratory system (Rrs). Rl and Edyn were measured during tidal breathing before and for 2 min after a deep inhalation and also at different lung volumes above and below functional residual capacity. Rrs was measured at functional residual capacity and at total lung capacity. Before MCh, saline infusion caused significant decrements of forced expiratory volume in 1 s, Vm(40), and Vp(40), but insignificantly affected lung volumes, elastic recoil, Rl, Edyn, and Rrs at any lung volume. Furthermore, saline infusion was associated with an increased response to MCh, which was not associated with significant changes in the ratio of Vm(40) to Vp(40). In conclusion, mild airflow obstruction and enhanced airway responsiveness were observed after saline, but this was not apparently due to altered elastic properties of the lung or inability of the airways to dilate with deep inhalation. It is speculated that it was likely the result of airway wall edema encroaching on the bronchial lumen.     

Segmental vascular resistances and compliances in dog lung

The segmental distribution of vascular resistances and compliances were evaluated in isolated blood perfused lung lobes using arterial, venous, and double-occlusion pressures and were compared with filtration midpoint capillary pressures (Pc,f). We separated total vascular resistance (RT) and compliance (CT) into large artery (Ra, Ca), large vein (Rv, Cv), and microvascular compartments (Rmc, Cmc) at base-line and increased vascular pressures and during infusions of histamine, serotonin, and norepinephrine. In control lobes, double-occlusion pressure (Pdo) closely approximated Pc,f at all vascular pressures. Pre- and postcapillary resistance were approximately equal when referenced to either Pc,f or Pdo. Although Rmc comprised 42% of RT and Cmc constituted 76% of CT, a twofold increase in base-line Pc,f caused RT to decrease to 67% and Rmc/RT to 29% of control values, whereas CT decreased to 87% and Cmc/CT decreased to 88% of control values over the same Pc,f range. Mean static CT was 2.25 +/- 0.09 ml X cmH2O-1. 100 g-1, whereas dynamic CT was 1.54 +/- 0.08 ml X cmH2O-1. 100 g-1, or only 68% of static vascular compliance. Drug infusions increased mean RT from 4.2- to 5.3-fold and significantly decreased both static and dynamic CT. Although all vascular segments were constricted, histamine affected primarily large veins, serotonin increased Ra greater than Rv, and norepinephrine constricted upstream and downstream vessels about equally. Increased Pc,f in the presence of these drugs decreased RT significantly in every case primarily through attenuation of the drug vasoconstrictor effect on Rmc and decreased CT primarily due to a decrease in Cmc, but increased Cmc/(Ca + Cv). Thus the microvascular compartment appears to be the major site of both fluid filtration and vascular compliance and contributes significantly to total vascular resistance. Drug infusions constricted large and small vessel compartments as defined here, but increased Pc,f attenuated microvascular vasoconstriction and to a lesser extent large vessel vasoconstriction resulting in a reduced microvascular resistance in both drug-treated and control lobes. This effect can be attributed to recruitment and/or distension of microvessels and distension of larger vessels.     

Significance of airway resistance for the pattern of breathing and lung volumes in exercising humans

The effects of increased airway resistance on lung volumes and pattern of breathing were studied in eight subjects performing leg exercise on a cycle ergometer. Airway resistance was changed 1) by increasing the density (D) of the respired gas by a factor of 4.2 and changing the inspired gas from O2 at 1.3 bar to air at 6 bar and 2) by increasing airway flow rates by exposing the subjects to incremental work loads of 0-200 W. Increased gas D caused a slower and deeper respiration at rest and during exercise and, at work loads greater than 120 W, depressed the responses of ventilation and mean inspiratory flow. Raised airway resistance induced by increases in D and/or airway flow rates altered respiratory timing by increasing the ratio of inspiratory time (TI) to total breath duration. Furthermore, analyses of the relationships between tidal volume and TI and between end-inspiratory volume and TI revealed elevation of Hering-Breuer inspiratory volume thresholds. We propose that this elevation, and hence exercise-induced increases of tidal volume, can largely be explained by previous observations that the threshold of the inspiratory off-switch mechanisms depends on central inspiratory activity (cf. C. von Euler, J. Appl. Physiol. 55: 1647-1659, 1983), which in turn increases with airway resistance (Acta Physiol. Scand. 120: 557-565, 1984).     

Laryngeal constriction in normal humans during experimentally induced bronchoconstriction

Changes in the size of the glottis with bronchoconstriction were assessed in six normal subjects following inhalation of histamine or methacholine. Measurements were made during both tidal breathing and panting at 2-3 Hz. The midexpiratory size of the glottis was decreased by a mean of 8% during bronchoconstriction compared with control during tidal breathing. Changes in midinspiratory size were inconsistent. During panting, the glottic size was unchanged from inspiration to expiration but decreased in 7 of 15 studies during bronchoconstriction. The decreases in expiratory size of the glottis during quiet breathing would lead to an elevated laryngeal resistance coupled with an increased lower airway resistance. Although this seems to be a paradoxical laryngeal response, it may contribute to maintaining hyperinflation during bronchoconstriction, thereby effectively enlarging the lower airways.     

Inhibitory effects of CO2 on airway defensive reflexes in enflurane-anesthetized humans

We investigated responses of respiration, blood pressure, and heart rate to tracheal mucosa irritation induced by injection of distilled water at three different levels of CO2 ventilatory drive in 11 spontaneously breathing female patients under a constant depth of enflurane anesthesia [1.1 minimum alveolar concentration (MAC)]. The airway irritation at the resting level of spontaneous breathing caused a variety of respiratory responses such as coughing, expiration reflex, apnea, and spasmodic panting, with considerable increases in blood pressure and heart rate. Although the latency of respiratory responses after water injection was much shorter than those of blood pressure and heart rate responses, blood pressure and heart rate responses, once elicited, were prolonged much longer than was the respiratory response. An increase in CO2 ventilatory drive decreased the degree and duration of respiratory, blood pressure, and heart rate responses to the airway irritation, whereas a decrease in CO2 ventilatory drive had the opposite effect on these responses. Our results indicate that changes in CO2 ventilatory drive can modify reflex responses of respiration, blood pressure, and heart rate to airway irritation.