Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma.

Allergic asthma is associated with airway epithelial cell mucous metaplasia and mucin hypersecretion, but the consequences of mucin hypersecretion on airway function are unclear. Recently, a peptide derived from the myristoylated alanine-rich C kinase substrate protein NH(2)-terminal sequence (MANS) was shown to inhibit methacholine (MCh)-induced mucin secretion from airway mucous cells by >90%. We studied the effect of intranasal pretreatment with this peptide on specific airway conductance (sGaw) during challenge with MCh in mice with allergen-induced mucous cell metaplasia. sGaw was noninvasively measured in spontaneously breathing restrained mice, using a double-chamber plethysmograph. Pretreatment with MANS peptide, but not a control peptide [random NH(2)-terminal sequence (RNS)], resulted in partial inhibition of the fall in sGaw induced by 60 mM MCh (mean +/- SE; baseline 1.15 +/- 0.06; MANS/MCh 0.82 +/- 0.05; RNS/MCh 0.55 +/- 0.05 cmH(2)O/s). The protective effect of MANS was also seen in mice challenged with allergen for 3 consecutive days to increase airway hyperresponsiveness, although the degree of protection was less (baseline 1.1 +/- 0.08; MANS/MCh, 0.65 +/- 0.06; RNS/MCh 0.47 +/- 0.03 cmH(2)O/s). Because routine sGaw measurement in mice includes nasal airways, the effectiveness of MANS was also confirmed in mice breathing through their mouths after nasal occlusion (baseline 0.92 +/- 0.05; MANS/MCh 0.83 +/- 0.06; RNS/MCh 0.61 +/- 0.03 cmH(2)O/s). In all instances, sGaw in the MANS-pretreated group was approximately 35% higher than in RNS-treated controls, and mucous obstruction accounted for approximately 50% of the MCh-induced fall in sGaw. In summary, mucin secretion has a significant role in airway obstruction in a mouse model of allergic asthma, and strategies to inhibit mucin secretion merit further investigation.     

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 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.     

Immunoglobulin E anaphylaxis in rabbits: mechanisms of pulmonary resistance and compliance changes

Factors causing changes in pulmonary resistance and dynamic compliance with immunoglobulin (Ig) E anaphylaxis in spontaneously breathing rabbits were assessed in ventilated rabbits using tantalum bronchography and wet-to-dry wt ratios. Ventilated rabbits demonstrated changes in resistance and compliance similar to spontaneously breathing rabbits. Chlorpheniramine pretreatment prevented increases in resistance but not decreases in compliance. Anaphylaxis constricted small (less than 1 mm) airways 20.9 +/- 16.0% (mean +/- SD) and intermediate (between 1 and 3 mm) airways 21.8 +/- 19.8%. Chlorpheniramine (10 mg/kg) prevented small airway changes and attenuated those in intermediate airways. Chlorpheniramine prevented histamine-induced constriction of small (23.6 +/- 15.7%) and intermediate (17.6 +/- 15.0%) airways. Lung wet-to-dry wt ratios were unchanged. Changes in resistance and compliance during rabbit IgE anaphylaxis are not due to changes in tidal volume or frequency. Histamine, via H1 receptors, is the principal mediator of pulmonary resistance increases but not dynamic compliance reductions. Chlorpheniramine-sensitive increases in resistance are caused by constrictions of intermediate and small airways, whereas the chlorpheniramine-resistant decrease in compliance is not caused directly by constriction of the smallest measurable airways (0.25 mm) or changes in lung water.     

Effects of elastase-induced emphysema on airway responsiveness to methacholine in rats

We examined the effects of elastase-induced emphysema on lung volumes, pulmonary mechanics, and airway responses to inhaled methacholine (MCh) of nine male Brown Norway rats. Measurements were made before and weekly for 4 wk after elastase in five rats. In four rats measurements were made before and at 3 wk after elastase; in these same animals the effects of changes in end-expiratory lung volume on the airway responses to MCh were evaluated before and after elastase. Airway responses were determined from peak pulmonary resistance (RL) calculated after 30-s aerosolizations of saline and doubling concentrations of MCh from 1 to 64 mg/ml. Porcine pancreatic elastase (1 IU/g) was administered intratracheally. Before elastase RL rose from 0.20 +/- 0.02 cmH2O.ml-1.s (mean +/- SE; n = 9) to 0.57 +/- 0.06 after MCh (64 mg/ml). A plateau was observed in the concentration-response curve. Static compliance and the maximum increase in RL (delta RL64) were significantly correlated (r = 0.799, P less than 0.01). Three weeks after elastase the maximal airway response to MCh was enhanced and no plateau was observed; delta RL64 was 0.78 +/- 0.07 cmH2O.ml-1.s, significantly higher than control delta RL64 (0.36 +/- 0.7, P less than 0.05). Before elastase, increase of end-expiratory lung volume to functional residual capacity + 1.56 ml (+/- 0.08 ml) significantly reduced RL at 64 mg MCh/ml from 0.62 +/- 0.05 cmH2O.ml-1.s to 0.50 +/- 0.03, P less than 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs.

We delivered controlled radio frequency energy to the airways of anesthetized, ventilated dogs to examine the effect of this treatment on reducing airway narrowing caused by a known airway constrictor. The airways of 11 dogs were treated with a specially designed bronchial catheter in three of four lung regions. Treatments in each of the three treated lung regions were controlled to a different temperature (55, 65, and 75 degrees C); the untreated lung region served as a control. We measured airway responsiveness to local methacholine chloride (MCh) challenge before and after treatment and examined posttreatment histology to 3 yr. Treatments controlled to 65 degrees C as well as 75 degrees C persistently and significantly reduced airway responsiveness to local MCh challenge (P < or = 0.022). Airway responsiveness (mean percent decrease in airway diameter after MCh challenge) averaged from 6 mo to 3 yr posttreatment was 79 +/- 2.2% in control airways vs. 39 +/- 2.6% (P < or = 0.001) for airways treated at 65 degrees C, and 26 +/- 2.7% (P < or = 0.001) for airways treated at 75 degrees C. Treatment effects were confined to the airway wall and the immediate peribronchial region on histological examination. Airway responsiveness to local MCh challenge was inversely correlated to the extent of altered airway smooth muscle observed in histology (r = -0.54, P < 0.001). We conclude that the temperature-controlled application of radio frequency energy to the airways can reduce airway responsiveness to MCh for at least 3 yr in dogs by reducing airway smooth muscle contractility.     

Methacholine-induced airway reactivity of inbred rats

Dose-response curves to inhaled aerosolized methacholine chloride (MCh) were obtained in anesthetized spontaneously breathing rats. Thirty rats (10/strain), randomly selected from highly inbred ACI, Lewis (L), and Brown Norway (BN) strains and 40 rats (20/strain) from similarly inbred Wistar-Furth (WF) and Buffalo (Buf) strains were studied. Airway responses were quantitated from changes in pulmonary resistance (RL) and airway reactivity was calculated as the dose of MCh required to increase RL to 150% (ED150RL) and 200% (ED200RL) of base line. There were no statistically significant differences in ED150RL and ED200RL among the five rat strains. Large interindividual variability was present as evidenced by 128-fold differences in ED150RL and ED200RL between the least and most sensitive animal of the same strain. In contrast, seven animals studied repeatedly on different days had values of ED150RL that differed by an average of only 2.9-fold (range 1.6-5.3). Thirteen rats that were studied on two occasions separated by an interval of 3 mo showed no systematic changes in airway reactivity. We conclude that airway reactivity to inhaled methacholine in anesthetized nose-breathing rats is not strain related, and despite animals of a given strain being genetically identical, the variability in airway reactivity within strains suggests that environmental rather than genetic factors are the major determinants of that reactivity.     

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.     

Effect of lung volume on interrupter resistance in cats challenged with methacholine

To examine the effects of changes in lung volume on the magnitude of maximal bronchoconstriction, seven anesthetized, paralyzed, tracheostomized cats were challenged with aerosolized methacholine (MCh) and respiratory system resistance (Rss) was measured at different lung volumes using the interrupter technique. Analysis of the pressure changes following end-inspiratory interruptions allowed us to partition Rss into two quantities with the units of resistance, one (Rinit) corresponding to the resistance of the airways and the other (Rdif) reflecting the viscoelastic properties of the tissues of the respiratory system as well as gas redistribution following interruption of flow. Rinit and Rdif were used to construct concentration-response curves to MCh. Lung volume was increased by the application of 5, 10, and 15 cmH2O of positive end-expiratory pressure. The curve for Rinit reached a plateau in all cats, demonstrating a limit to the degree of MCh-induced bronchoconstriction. The mean value of Rinit (cmH2O.ml-1.s) for the group under control conditions was 0.011 and rose to 0.058 after maximal bronchoconstriction; the volume at which the flow was interrupted was 11.5 +/- 0.5 (SE) ml/kg above functional residual capacity (FRC). It then fell progressively to 0.029 at 21.2 +/- 0.8 ml/kg above FRC, 0.007 at 35.9 +/- 1.3 ml/kg above FRC, and 0.005 at 52.0 +/- 1.8 ml/kg above FRC. Cutting either the sympathetic or parasympathetic branches of the vagi had no significant effect on the lung volume-induced changes in MCh-induced bronchoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of the dose-response behavior of canine airways and parenchyma

We compared the histamine responsiveness of canine airways and parenchymal tissues in six anesthetized paralyzed open-chest mongrel dogs, partitioning total lung resistance (RL) into airway resistance (Raw) and tissue viscance (Vti). Pressure was measured during tidal breathing (frequency was 0.3 Hz) at the trachea and in three alveolar regions by use of alveolar capsules. Measurements were taken before and after the delivery of increasing concentrations of aerosolized histamine (0.1-30 mg/ml). We found that Vti accounted for 78 +/- 8% of RL under base-line conditions; this proportion remained relatively constant throughout the histamine concentration-response curve. There was a significant correlation between percent change in Vti and percent change in Raw at all levels of histamine-induced constriction (P less than 0.001). Moreover, the sensitivity of the tissues and airways (defined as the concentration of histamine required to double resistance) was remarkably similar. We conclude that, at this frequency of ventilation, Vti accounts for the major portion of RL both under base-line conditions and after histamine-induced constriction. Although increases in RL cannot be attributed solely to events occurring in the airways, the close correlation between changes in Raw and Vti and the similar sensitivities of the two support the use of indexes reflecting changes in airway caliber as an indicator of overall lung histamine responsiveness.     

Tissue viscance during induced constriction in rabbit lungs: morphological-physiological correlations.

Tissue viscance (Vti), the pressure drop across the lung tissues in phase with flow, increases after induced constriction. To gain information about the possible site of response, we induced increases in Vti with methacholine (MCh) and attempted to correlate these changes with alterations in lung morphology. We measured tracheal (Ptr) and alveolar pressure (PA) in open-chest rabbits during mechanical ventilation [frequency = 1 Hz, tidal volume = 5 ml/kg, positive end-expiratory pressure (PEEP) = 5 cmH2O] under control conditions and after administration of saline or MCh (32 or 128 mg/ml) aerosols. We calculated lung elastance (EL), lung resistance (RL), Vti, and airway resistance (Raw) by fitting the equation of motion to changes in Ptr and PA. The lungs were then frozen in situ with liquid nitrogen (PEEP = 5 cmH2O), excised, and processed using freeze substitution techniques. Airway constriction was assessed by measuring the ratio of the airway lumen (A) to the ideally relaxed area (Ar). Tissue distortion was assessed by measuring the mean linear intercept between alveolar walls (Lm), the standard deviation of Lm (SDLm), and an atelectasis index (ATI) derived by calculating the ratio of tissue to air space using computer image analysis. RL, Vti, and EL were significantly increased after MCh, and Raw was unchanged. A/Ar, Lm, SDLm, and ATI all changed significantly with MCh. Log-normalized change (% of baseline) in Vti significantly correlated with A/Ar (r = -0.693), Lm (r = 0.691), SDLm (r = 0.648), and ATI (r = 0.656). Hence, changes in lung tissue mechanics correlated with changes in morphometric indexes of parenchymal distortion and airway constriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of muscle activity on the elastance of the upper airway of rabbits

This study sought to assess the effect of variations in upper airway muscle activity on upper airway pressure-volume properties. Upper airway elastance, closing pressure, and reserve volume were measured in the isolated upper airways of anesthetized rabbits under control conditions and after administration of gallamine (2 mg/kg iv) or after 10 min of spontaneous respiration of 7% CO2 in O2. Administration of gallamine to seven animals was associated with a fall in reserve volume from 0.94 +/- 0.24 to 0.69 +/- 0.17 (95% confidence interval) ml (P less than 0.01) and of closing pressure from -7.53 +/- 0.23 to -5.75 +/- 1.05 cmH2O (P less than 0.01), but airway elastance did not change significantly. Hypercapnia in seven animals was associated with a rise in elastance from 7.06 +/- 0.91 to 7.67 +/- 0.86 cmH2O/ml (P less than 0.001) and in reserve volume from 0.68 +/- 0.06 to 0.86 +/- 0.13 ml (P less than 0.05). Closing pressure also changed from -5.88 +/- 0.94 to -7.92 +/- 1.85 cmH2O. This change was correlated with the change in reserve volume but not with the change in elastance. In three animals exposed to hypercapnia, return to room air breathing was associated with return of elastance, reserve volume, and closing pressure to control levels. It is concluded that muscle activity in the upper airway affects both the size and elastance of the airway, but the dominant mechanism by which upper airway muscles increase the resistance of the upper airway to collapse is by increasing airway volume.     

Assessment of heterogeneous airway constriction in dogs: a structure-function analysis

Obstructive lung diseases are often characterized by heterogeneous patterns of bronchoconstriction, although specific relationships between structural heterogeneity and lung function have yet to be established. We measured respiratory input impedance (Zrs) in eight anesthetized dogs using broadband forced oscillations at baseline and during intravenous methacholine (MCh) infusion. We also obtained high-resolution computed tomographic (HRCT) scans in 4 dogs and identified 20-30 individual airway segments in each animal. The Zrs spectra and HRCT images were obtained before and 5 min following a deep inspiration (DI) to 35 cmH(2)O. Each Zrs spectrum was fitted with two different models of the respiratory system: 1) a lumped airways model consisting of a single airway compartment, and 2) a distributed airways model incorporating a continuous distribution of airway resistances. For the latter, we found that the mean level and spread of airway resistances increased with MCh dose. Whereas a DI had no effect on average airway resistance during MCh infusion, it did increase the level of airway heterogeneity. At baseline and low-to-moderate doses of MCh, the lumped airways model was statistically more appropriate to describe Zrs in the majority of dogs. At the highest doses of MCh, the distributed airways model provided a superior fit in half of the dogs. There was a significant correlation between heterogeneity assessed with inverse modeling and the standard deviation of airway diameters obtained from HRCT. These data demonstrate that increases in airway heterogeneity as assessed with forced oscillations and inverse modeling can be linked to specific structural alterations in airway diameters.     

Comparison of upper and lower airway responses of two sensitized rat strains to inhaled antigen.

The purpose of the study was to investigate the relationships between upper airways responses and pulmonary responses of two strains of highly inbred rats to inhaled antigen. To do this we measured the upper and lower airways resistance for 60 min after challenge of Brown-Norway rats (BN; n = 13) and an inbred rat strain (MF; n = 11), derived from Sprague-Dawley, with aerosolized ovalbumin (OA). Rats were actively sensitized with OA (1 mg sc) using Bordetella pertussis as an adjuvant. Two weeks later the animals were anesthetized and challenged. Tracheal pressure, esophageal pressure, and airflow were measured, from which total pulmonary resistance was partitioned into upper airway and lower pulmonary resistance (RL). The peak upper airway response to inhaled OA was similar in BN (1.89 +/- 0.66 cmH2O.ml-1.s; n = 7) and MF (2.85 +/- 0.68 cmH2O.ml-1.s; n = 6). The lower airway response to OA challenge was substantially greater in BN, and RL changed from 0.07 +/- 0.01 to 0.34 +/- 0.13 (n = 6; P < 0.05). The MF did not have any significant increase in RL after challenge; the baseline RL was 0.12 +/- 0.02 and only reached a peak value of 0.15 +/- 0.05 (n = 5; P = NS). Lower airway responsiveness of BN (n = 10) to serotonin, an important mediator early allergic airway responses, was similar to MF (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of transpulmonary pressure on airway diameter and responsiveness of immature and mature rabbits.

We previously demonstrated that airway responsiveness is greater in immature than in mature rabbits; however, it is not known whether there are maturational differences in the effect of transpulmonary pressure (Ptp) on airway size and airway responsiveness. The relationship between Ptp and airway diameter was assessed in excised lungs insufflated with tantalum powder. Diameters of comparable intraparenchymal airway segments were measured from radiographs obtained at Ptp between 0 and 20 cmH(2)O. At Ptp > 8 cmH(2)O, the diameters were near maximal in both groups. With diameter normalized to its maximal value, changing Ptp between 8 and 0 cmH(2)O resulted in a greater decline of airway caliber in immature than mature airways. The increases in lung resistance (RL) in vivo at Ptp of 8, 5, and 2 cmH(2)O were measured during challenge with intravenous methacholine (MCh: 0.001-0.5 mg/kg). At Ptp of 8 cmH(2)O, both groups had very small responses to MCh and the maximal fold increases in RL did not differ (1.93 +/- 0.29 vs. 2.23 +/- 0.19). At Ptp of 5 and 2 cmH(2)O, the fold increases in RL were greater for immature than mature animals (13.19 +/- 1.81 vs. 3.89 +/- 0.37) and (17.74 +/- 2.15 vs. 4.6 +/- 0.52), respectively. We conclude that immature rabbits have greater airway distensibility and this difference may contribute to greater airway narrowing in immature compared with mature rabbits.     

Airway constriction measured from tantalum bronchograms in conscious mice in response to methacholine

A single-projection X-ray technique showed an increase in functional residual capacity (FRC) in conscious mice in response to aerosolized methacholine (MCh) with little change in airway resistance (Raw) measured using barometric plethysmography (Lai-Fook SJ, Houtz PK, Lai Y-L. J Appl Physiol 104: 521-533, 2008). The increase in FRC presumably prevented airway constriction by offsetting airway contractility. We sought a more direct measure of airway constriction. Anesthetized Balb/c mice were intubated with a 22-G catheter, and tantalum dust was insufflated into the lungs to produce a well-defined bronchogram. After overnight recovery, the conscious mouse was placed in a sealed box, and bronchograms were taken at maximum and minimum points of the box pressure cycle before (control) and after 1-min exposures to 25, 50, and 100 mg/ml MCh aerosol. After overnight recovery, each mouse was studied under both room and body temperature box air conditions to correct for gas compression effects on the control tidal volume (Vt) and to determine Vt and Raw with MCh. Airway diameter (D), FRC, and Vt were measured from the X-ray images. Compared with control, D decreased by 24%, frequency decreased by 35%, FRC increased by 120%, and Raw doubled, to reach limiting values with 100 mg/ml MCh. Vt was unchanged with MCh. The limiting D occurred near zero airway elastic recoil, where the maximal contractility was relatively small. The conscious mouse adapted to MCh by breathing at a higher lung volume and reduced frequency to reach a limit in constriction.     

Neonatal calves develop airflow limitation due to chronic hypobaric hypoxia

Neonates and infants presenting with pulmonary hypertension and chronic hypoxia often exhibit airway obstruction. To investigate this association, we utilized a system in which neonatal calves are exposed to chronic hypobaric hypoxia and develop severe pulmonary hypertension. For the present study, one of each pair of six age-matched pairs of neonatal calves was continuously exposed to hypobaric hypoxia at 4,500 m (CH); the other remained at 1,500 m. At 2 wk of age, mean pulmonary arterial pressure (MPAP), dynamic lung compliance (Cdyn), resistance (RL), and static respiratory system compliance (Crs) were measured at 4,500 m in both CH and control calves exposed acutely to hypoxia (C). These measurements were repeated after cumulative administrations of nebulized methacholine (MCh). Tissues were removed for histological examination and assessment of bronchial ring contractility to MCh and KCl. After 2 wk of hypobaric hypoxia, MPAP (C 35 +/- 1.7 vs. CH 120 +/- 7 mmHg, P less than 0.001) and RL (C 2.64 +/- 0.16 vs CH 4.99 +/- 0.47 cmH2O.l-1s, P less than 0.001) increased. Cdyn (C 0.100 +/- 0.01 vs. CH 0.082 +/- 0.007 l/cmH2O) and Crs (CH 0.46 +/- 0.003 vs. C 0.59 +/- 0.009 l/cmH2O) were not significantly different. Compared with airways of C calves, airways of CH animals did not exhibit in vivo or in vitro MCh hyperresponsiveness; however, in vitro contractility to KCl of airways from CH animals was significantly increased. Histologically, airways from the CH calves showed increases in airway fibrous tissue and smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interdependence of bronchial circulation and clearance of 99mTc-DTPA from the airway surface.

The extent to which the systemic vasculature is involved in soluble-particle uptake in the conducting airways has not been studied extensively. In anesthetized, ventilated sheep, 6-10 microl of technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) was delivered through a microspray nozzle to a fourth-generation airway. Perfusion of the cannulated bronchial artery was varied between control flow (0.6 ml x min(-1) x kg(-1)), high flow (1.8 ml x min(-1) x kg(-1)) or no flow (the infusion pump was stopped). Airway retention of the radioactive tracer was monitored using gamma camera imaging, and venous blood was sampled. During control perfusion, tracer retention at the site of deposition at 30 min averaged 20 +/- 6% (n = 7). With no flow, retention was significantly elevated to 32 +/- 8% (P = 0.03). In another group of sheep (n = 5) with a control retention of 13 +/- 4%, high flow resulted in an increase in tracer (25 +/- 4%; P = 0.04). Maximum blood uptake of tracer was calculated by estimating circulating blood volume and averaged 16% of total activity during control flow. Only during high-flow conditions was 99mTc-DTPA in the blood decreased (10%; P = 0.04). Most of the tracer was cleared by mucociliary clearance as visualized by imaging. This component was substantially decreased during no flow. The results demonstrate that both decreased and increased airway perfusion limit removal of soluble tracer applied to the conducting airways.     

Late-phase bronchial vascular responses in allergic sheep

Sheep were classified on the basis of their airway response to Ascaris suum antigen aerosols as allergic or nonsensitive. Allergic sheep were classed as acute or dual responders. Acute responders had only an immediate increase in mean airflow resistance after antigen, whereas dual responders had an immediate and late-phase (6-8 h after antigen challenge) increase in mean airflow resistance; nonsensitive sheep had minimal airway responses to antigen (less than 30% increase from base line). The sheep were anesthetized 2 wk later and, after a left thoracotomy, were challenged with antigen to determine bronchial vascular responses; bronchial artery blood flow was measured with an electromagnetic flow probe. Airway responses to antigen aerosol challenge were similar in the anesthetized and conscious animals. The mean fall in bronchial vascular resistance (BVR) immediately after antigen challenge was similar in acute and dual responders (41 +/- 7 and 47 +/- 9% of base line, respectively). In dual responders, late-phase airway responses were preceded by a significant increase from base line in Qbr and a fall in bronchovascular resistance (BVR). The mean fall in BVR 6-8 h after antigen challenge in documented dual responders was significantly different from bronchial vascular responses in acute responders (59 +/- 3 vs. 89 +/- 10%, respectively). Sheep without airway responses to A. suum had no significant changes in bronchial hemodynamics or airways mechanics. Late-phase-associated changes in BVR are a specific response to antigen challenge and may be a sensitive index of mediators being released.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.