Mechanisms of limited airway dimension with lung inflation

Airways distend with each inspiration, while a sigh or deep inspiration (DI) leads to a significant or a maximum distension of the airways. Distension of the airways is thought to play an important role in maintaining airway patency. Limited distension of the airways with lung inflation may be a major factor in certain lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). High resolution computed tomography (HRCT) has gained wide acceptance as a diagnostic and investigational radiological tool for the evaluation of airway function. HRCT has been used to measure dynamic changes in airway caliber in vivo that are not detectable by conventional global lung measurements such as airway and lung resistance. HRCT is uniquely capable of imaging and quantifying airway size at different lung volumes. The current paper reviews the use of HRCT to examine the role of lung inflation on airway distension in animal models, and discusses potential mechanisms for limited distension of the airways with lung inflation in individuals with asthma and COPD.     

Enhanced aerosol deposition in the lung with mild airways obstruction

We investigated the sensitivity of aerosol deposition to airways obstruction by measuring total deposition fraction of inert aerosol in normal conscious sheep (n = 6) after challenging cholinergic agent, pilocarpine (PL) (0.5 mg/kg intravenously) with and without a prior challenge of beta 2-adrenergic agonist, terbutaline sulfate (TS) (0.025 mg/kg subcutaneously). Aerosol deposition was measured by a light-scattering aerosol photometer in situ while sheep rebreathed 1.0-micron-diameter inert oil droplets from a 0.2-L collapsible bag at a rate of 30 breaths/min. Total accumulated deposition at the fifth breath (AD5) as a percentage of initial aerosol concentration was determined and compared with mean pulmonary airflow resistance (RL). After PL, both AD5 and RL increased significantly from baseline values by 51 +/- 9% and 597 +/- 118% (mean +/- SE), respectively, whereas AD5 and RL decreased significantly by 16 +/- 4% and 34 +/- 6%, respectively after TS (p less than 0.05). After PL subsequent to TS (TS-PL), AD5 increased in all six sheep by 33 +/- 7% from post-TS values (p less than 0.05). However, RL did not change from post-TS values. Greater changes in RL than in AD5 after PL (bronchoconstriction) or TS (bronchodilation) suggest a greater sensitivity of RL than AD5 to airway patency in the large airways. Lack of increase of RL after TS-PL indicates that bronchoconstrictive effect of PL was blocked by prior challenge with TS. Therefore, the increase in AD5 after TS-PL may be related to the peripheral airway obstructions which might have been caused by increased secretions induced by a potent secretagogue PL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of airway narrowing caused by inhaled platelet-activating factor. Role of airway microvascular leakage

In order to study the mechanism of airway narrowing after inhaled platelet-activating factor (PAF) we measured concomitant changes in lung resistance (RL) and in airway microvascular leakage in anesthetized guinea pigs. RL and its recovery after hyperinflation at 5 min were measured until 6 min after PAF aerosol (0.1, 0.3, 1, and 3 mM), and in the case of 3 mM PAF also until 10 min. Microvascular leakage in trachea, main bronchi, and proximal and distal intrapulmonary airways was determined by measurement of extravasated Evans blue dye content. For comparison, the responses to inhaled histamine (3 mM) and 5-hydroxytryptamine (5HT) (3 mM), which act directly on airway smooth muscle, were also examined. Inhaled PAF increased RL dose-dependently, with a maximal response (peak RL) at 4 min after the inhalation, whereas the response to histamine or 5HT was maximal within a few seconds after the inhalation. Peak RL (cm H2O/ml/s) was significantly less after PAF (1.03 +/- 0.09) than after histamine (8.39 +/- 1.07) or 5HT (18.3 +/- 6.48), although there was no significant difference in RL after hyperinflation (recovery RL). No additional increase in RL was seen between 5 and 10 min after exposure. PAF caused a dose-dependent increase in Evans blue dye extravasation; 3 mM PAF induced significantly higher leakage than did histamine or 5HT at all airway levels at 6 min. PAF did not cause any additional extravasation of Evans blue dye at 10 min compared with that at 6 min after exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bronchoconstrictor reactivity to NKA in allergic dogs: a comparison to histamine and methacholine

Airway hyperresponsiveness to neurokinin A (NKA) occurs in inflammatory airway diseases like asthma. In this study, bronchoconstrictor reactivity to NKA was measured in beagle dogs neonatally sensitized to and challenged with ragweed. Comparisons were made to histamine and methacholine. Lung resistance (R(L)) and dynamic lung compliance (C(Dyn)) were measured in anesthetized, spontaneously breathing dogs before and after aerosol challenge with NKA, histamine or methacholine. The concentration of these agents increasing R(L)by 25% above baseline (PC(25)) was calculated before and 24 h after aerosolized ragweed challenge. Before ragweed, the bronchoconstrictor reactivity to NKA was four-fold higher in ragweed-sensitized dogs (PC(25)=0.036+/-0.006%) compared to non-sensitized controls (PC(25)=0.177+/-0.030%, P<0.05). On the other hand, there was no difference in the bronchoconstrictor reactivity to histamine or methacholine between these two groups. Twenty-four hours after ragweed challenge to sensitized dogs, NKA reactivity was unchanged from pre-ragweed values but histamine and methacholine reactivity was increased by 2-3-fold. These results demonstrate airway hyperresponsiveness to NKA, histamine and methacholine in allergic beagle dogs although hyperresponsiveness to NKA exists in these allergic dogs before an antigen challenge. This animal model may prove to be useful to evaluate the role of tachykinins in hyperractive airway diseases. Copyright Academic Press.     

Reversibility of induced bronchoconstriction by deep inspiration in asthmatic and normal subjects

Five normal and five asthmatic subjects underwent a progressive methacholine provocation study. At each concentration inspiratory pulmonary resistance (RL) was measured, as well as isovolumic maximal flow and residual volume from both partial and complete forced expirations. Results were compared over the RL range of 6-11 cmH2O.1-1.S-1. The reversibility of bronchoconstriction by deep inspiration was quantified as the ratio of the flow increase to potential maximal increase; the reversibility of gas trapping was the ratio of decrease in residual volume to potential maximal decrease. The reversibility of bronchoconstriction did not differ between the groups. In contrast, the reversibility of gas trapping was smaller in asthmatic subjects (21 +/- 17%) than in normals (84 +/- 6%). As gas trapping reflects airway closure, our findings suggest that during induced bronchoconstriction airway closure is more resistant to the effects of deep inspiration in asthmatic than in normal subjects but the reversibility of bronchoconstriction by deep inspiration is not different.     

Comparative effects of volume history on bronchoconstriction induced by hyperventilation and methacholine in asthmatic subjects

The aim of this study was to find out if bronchodilatation following deep inspiration can be induced by the inhalation of a "natural" stimulus (hyperventilation of cold dry air), and if the effect is similar to that induced by methacholine. After baseline assessment of lung resistance (RL), 10 asthmatic subjects were asked to inhale cold dry air for 3 min. RL was monitored continuously for 3-4 min, at which time subjects were asked to take a fast deep inspiration. After recovery, the manoeuvre was repeated and RL was reassessed. The manoeuvre was then repeated a third time. After functional recovery, progressive doses of methacholine were inhaled until the increase in RL was comparable to that obtained after hyperventilation (56 +/- 16% and 65 +/- 24%, respectively, mean +/- SD, NS). The same deep inspiration manoeuvre was repeated three times with recovery as after hyperventilation of cold dry air. Maximum changes in RL were not significantly different after each of the three manoeuvres for either type of bronchoconstriction. The mean fall in RL was 14.2 +/- 9.9% after hyperventilation and 16.4 +/- 10.5% after methacholine. There was a satisfactory correlation (r = 0.80, p less than 0.01) between the bronchodilatation after deep inspiration for both types of stimuli. We conclude that the bronchodilator effect of deep inspiration is no different using either a pharmacological stimulus (methacholine) or a "natural" stimulus (hyperventilation of unconditioned air). These results show that assessing the response to hyperventilation with manoeuvres requiring deep inspiration, forced expiratory volume in one second (FEV1) may alter airway tone in a way similar to pharmacological stimuli.     

Airway hyperreactivity in patients undergoing lung and heart/lung transplantation

To assess airway reactivity in lung transplant patients, three heart/lung, three double lung, and eight single lung transplant patients underwent airway challenge tests. All patients were assessed by methacholine aerosol challenge and thirteen were also assessed by histamine aerosol challenge at least three months after transplant surgery. The airways of patients with bilaterally denervated lungs (heart/lung and double lung transplants) were significantly more reactive to both methacholine and histamine (p less than 0.01) than were the airways of patients with unilaterally denervated (single lung transplants) lungs. Inflammatory changes in the airway mucosal biopsies were minimal in three patients and absent in all others. These studies raise questions about the role of central innervation in the maintenance of normal airway function as well as the mechanisms of action of both methacholine and histamine in causing bronchoconstriction.     

Distribution of airway contractile responses within the major diameter bronchi during exogenous bronchoconstriction

The distribution of bronchoconstrictor responses within airway generations zero to 6 was studied by tantalum bronchography during exogenous bronchoconstriction with methacholine (MCh), prostaglandin F2 alpha (PGF2 alpha), norepinephrine (NE), and the thromboxane mimetic U-46619 [(15S)-hydroxyl-11 alpha,9 alpha-(epoxymethano)prosta-5Z, 13E-dienoic acid] in 12 mongrel dogs undergoing vagotomy and beta-adrenergic blockade. Dose-response curves to each agonist were generated in random order, and tantalum bronchograms and simultaneous measurements of pulmonary resistance (RL) and dynamic pulmonary compliance (Cdyn) were obtained at the plateau of the response of each dose of agonist after intravenous (iv) infusion. At 5 X 10(-7) mol/kg, NE (after beta-adrenergic blockade) caused an increase to 254 +/- 27.3%, PGF2 alpha to 368 +/- 50.0%, U-46619 to 522 +/- 98.5%, and MCh to 1,204 +/- 173% of baseline in RL. However, airway diameter changes within the major diameter airways varied substantially for each agonist. Methacholine caused substantial contraction in all airways. Neither NE nor U-46619 caused significant airway narrowing in generations zero or 1, although both agonists caused greater than 30% narrowing in sixth generation airways. Prostaglandin F2 alpha (5 X 10(-7) mol/kg) cause an increase in RL of greater than 350%; however, this was accompanied by an approximately 10% increase (dilation) in airway diameter in generation 1 through generation 4 airways and an approximate 25% narrowing in generation 6 airways. We demonstrate that both alpha-adrenergic agonists and thromboxane analog cause substantial bronchoconstriction in situ in the central air-ways of the lung.(ABSTRACT TRUNCATED AT 250 WORDS)     

Partitioning of pulmonary responses to inhaled methacholine in subjects with asymptomatic asthma.

To partition the central and peripheral airway resistance, a catheter-tip micromanometer sensing lateral pressure of the airway was wedged into the right lower lobe of a bronchus with a 3 mm inner diameter in 10 patients with asymptomatic asthma. We simultaneously measured mouth flow, transpulmonary pressure (PL) and intra-airway lateral pressure during tidal breathing. Total pulmonary resistance (RL) was calculated from PL and mouth flow, and central airway resistance (RC) was calculated from intra-airway lateral pressure and mouth flow. Peripheral airway resistance (Rp) was obtained by subtraction of RC from RL. Therefore, our measurement of Rp included lung tissue resistance. The technique permitted identification of the site of changes in airway resistance. The baseline values of resistances were 2.3 +/- 0.2 cm H2O/L/s in RL, 1.5 +/- 0.1 cm H2O/L/s in RC, and 0.8 +/- 0.1 cm H2O/L/s in Rp, respectively. To determine the site of airway hyperresponsiveness, dose-response curves of central, peripheral, and total airways to inhaled methacholine were separately constructed. Bronchial responsiveness was evaluated by a log methacholine unit requiring a 35% decrease (PC35) and a 50% decrease (PC50) in pulmonary conductance (a reciprocal of RL). We calculated the increase of resistances in total (delta RL), central (delta RC), and peripheral (delta Rp) airways from the baseline values at either PC35 or PC50.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potential mechanism of hyperresponsive airways

It has been known for many years that the response of asthmatic subjects to a deep inspiration differs from that observed in normal healthy subjects. A deep inspiration causes a decrease in airway resistance in normal subjects, whereas asthmatics demonstrate either no change or a slight increase in airway resistance. It has been suggested by several investigators that the inability to dilate airways during lung inflation may be a primary defect in asthma. One study (Skloot and colleagues, J. Clin. Invest. 1995;96:2393- 2403) showed that in the absence of a deep inspiration during methacholine (MCh) challenge, normal subjects had a greatly exaggerated and sustained response to this agonist. It was suggested that asthmatic airways could be modeled by this condition in normal, subjects. Other investigators, however, suggest that there are more intrinsic differences between the responses to lung inflation in airways from asthmatic and normal subjects (Brusasco and colleagues, J. Appl. Physiol. 1999;87:567-573). Resolution of this controversy requires the ability to assess the responses of airways directly, but unfortunately conventional pulmonary function tests in human subjects are not specific enough to allow this evaluation. In the present study, we have performed experiments using a direct imaging approach that allows us to obtain measurements of airway and parenchymal dimensions that can be used to test the responses of individual airways to deep inspiration in vivo. Our results show that the presence of normal tidal stresses allows airway smooth muscle to respond normally to deep inspirations. Removing tidal stresses at FRC after MCh challenge is sufficient to change the normal dilatory response to deep inspiration into an abnormal one of contraction. Altered sensitivity of airway smooth muscle to normal tidal stresses thus may be operative in the development of the asthmatic pathology.     

Morphometry of the airways during late responses to antigen challenge in the rat

To quantitate the structural changes in the airways that contribute to the late bronchial response (LR) to antigen challenge we killed six Brown-Norway rats, sensitized to ovalbumin (OA) and challenged by aerosol, during the LR and compared the dimensions of the intraparenchymal airways with those of six control animals. Lungs were rapidly frozen with liquid nitrogen and fixed in Carnoy's solution. Paraffin sections were stained with hematoxylin-phloxine-saffron. At the time of the LR (382 +/- 39 min after OA challenge), RL increased from the baseline value (0.067 +/- 0.034 cm H2O.ml-1.s) by 0.107 +/- 0.03 cm H2O.ml-1.s (p less than 0.05). RL did not change significantly in the control rats. The lumen size and the wall area of all membranous airways were measured and were corrected for airway size by dividing by the basement membrane length squared (BM2). There was no increase in airway wall area in OA-challenged animals. However, the lumen of large airways (BM: 2.0 to 2.99 mm) was significantly less for the OA-challenged animals (0.039 +/- 0.0055 mm2) than for the control animals (0.058 +/- 0.0063 mm2; p less than 0.05). In six additional rats, the distribution of mast cells (MC) in the bronchial tree was determined. Tissues were fixed with Carnoy's solution and stained with a modified May-Grunwald-Giemsa stain. There were significantly more MC in the large airways than in medial or small airways. We conclude that smooth muscle constriction of large airways and not airway wall edema accounts for the LR in the rat. The distribution of the mast cells corresponds closely to the site of bronchoconstriction.     

Spasmodic croup in the adult

Recurrent inspiratory stridor, for which there appears to be no organic basis, can present a serious medical problem. We measured the changes in cross-sectional area of the glottic aperture during the respiratory cycle in a patient with recurrent inspiratory stridor when she was well, during a spontaneous attack, and during one induced with histamine aerosol. The glottis was visualized using a fiberoptic bronchoscope passed transnasally and attached to a video camera and tape recorder. During stridor there was marked constriction of the glottis on inspiration and phase reversal of the normal movements of the vocal cords with respect to respiration. Intermittent positive pressure ventilation (IPPV) and continuous positive airway pressure (CPAP) applied during stridor, in the absence of inspiratory effort, reversed the glottic narrowing. Pulmonary resistance (RL) on inspiration was elevated during stridor and returned to normal during IPPV and CPAP. Expiratory RL was normal throughout. Our results show that stridor in this patient was due to dynamic inspiratory constriction of the vocal cords. Glottic constriction could be induced by histamine aerosol and reversed when lung inflation was unaccompanied by inspiratory effort during IPPV and CPAP. Recognition and appropriate management of this condition may avoid potentially dangerous therapeutic interventions.     

Increase in luminal mast cell and epithelial damage may account for increased airway responsiveness after viral infection in dogs

To elucidate the mechanisms of airway hyperresponsiveness induced by viral infection, we examined histologically and analyzed bronchoalveolar lavage (BAL) fluid using dogs infected with influenza C and noninfected control dogs. Airway responsiveness was assessed as inhaled acetylcholine concentration required to increase pulmonary resistance by 5 cm H2O/L/s (ACh PC). Airway responsiveness was determined before and 2 wk after virus or vehicle inoculation in infected and control dogs, and BAL and histologic studies were performed after the final challenge. Differential cell numbers and histamine concentration were determined in the BAL fluids of both groups. The ACh PC of control dogs did not change with the vehicle inoculation. However, that of infected dogs decreased two to five times as much as their initial value with viral infection. Histologic studies revealed diffuse epithelial damage in the central airways of infected dogs, but infiltrated cell counts within the airway tissue of both groups were not significantly different. From BAL analysis, mast cell number and the histamine concentration of infected dogs increased significantly compared with those of control dogs (3.1 +/- 0.4 x 10(5) versus 0.9 +/- 0.3 x 10(5) cells/ml and 7.3 +/- 1.7 versus 1.9 +/- 0.5 ng/ml, respectively). Luminal mast cell number and epithelial damage score in each dog was correlated with the increase in airway responsiveness. These findings indicate that airway inflammation in virus-induced hyperreactive dogs is characterized by epithelial damage and luminal increase in mast cells and related mediators, and these changes may be related to the appearance of virus-induced airway hyperreactivity.     

Kinetics of the recovery from bronchial obstruction due to hyperventilation of cold air in asthmatic subjects

The timecourse of recovery from bronchial obstruction due to inhaled cold air was studied in eight adult asthmatic subjects. On the first visit, bronchial responsiveness to inhaled histamine was assessed. On the other two visits, after assessment of baseline lung resistance (RL) and spirometry, dry cold (-20 degrees C) air was inhaled for three minutes. RL was monitored continuously until its return to baseline +/- 20%. The baseline concentration of histamine causing a 20% fall in FEV1 (PC20) varied from 0.03 to 5.9 mg.ml-1. The mean maximum increase in RL was 2-fold (2.03 +/- 0.41) and was reached 2-11 min after the challenge. RL values were linearly correlated to time (r2 values greater than 0.80 in 14/16 instances). The two slopes of recovery were not significantly different. Slopes of recovery and total time of recovery (14-55 min) varied greatly between subjects. No relationship was found between baseline airway calibre, bronchial hyperresponsiveness and maximal increase in baseline RL on the one hand and the slopes of recovery on the other.     

Variability of pulmonary responsiveness to aerosolized histamine in normal rabbits

Considerable between-subject variability in pulmonary responsiveness to histamine has been reported in normal human subjects, dogs, guinea pigs, and rhesus monkeys, but rabbits have not been studied. We determined the between- and within-rabbit variability of pulmonary histamine responsiveness in 34 anesthetized and mechanically ventilated New Zealand White rabbits. In 30 rabbits, 5 breaths of aerosolized histamine were delivered in 9 increasing concentrations ranging from 0.01 to 100 mg/ml. Eleven of 30 rabbits were rechallenged with histamine on 1-4 additional occasions over a 3-week period. In the remaining 4 rabbits, 9 doses of distilled H2O were aerosolized to determine the degree of spontaneous variability in measurements of lung resistance (RL) and dynamic lung compliance (Cdyn). We defined an increase in RL of greater than 50% of baseline (TD50RL) and a decrease in Cdyn of greater than 25% of baseline (TD25Cdyn) as being significant based on observations in these 4 rabbits. These limits exceeded the 99.9 percentile of spontaneous variability in RL and Cdyn. Pulmonary responsiveness to histamine varied widely, with a greater than 10,000-fold range in TD50RL and a 1,000-fold range in TD25Cdyn between the most and least sensitive rabbits. The variability of this responsiveness was log-normally distributed. It was not correlated with age, sex, or baseline RL and Cdyn. In contrast, within-rabbit responses to histamine challenge were quite reproducible. Five of 30 rabbits were killed at the conclusion of their histamine challenges for pathologic examination of their lungs. No evidence of airway inflammation was found.(ABSTRACT TRUNCATED AT 250 WORDS)     

How many spirograms for a histamine challenge?

Several reports have shown that a prior deep inspiration exerts a blunting effect on pharmacologically induced bronchoconstriction. Inspiration to total lung capacity is a mandatory requirement for valid determination of the FEV1, and thus, the FEV1 may underestimate the magnitude of induced airway obstruction. The present study was designed to assess the effect that the performance and separate analysis of 2 consecutive FEV1 maneuvers (FEV(1)1, FEV(1)2), obtained at different levels of histamine-induced bronchoconstriction, may have on the final interpretation of a histamine challenge. Eight asymptomatic nonsmoking asthmatics (mean age, 24 yr; range, 19 to 27 yr) underwent a total of 16 histamine challenges. Paired FEV1 measurements (FEV(1)1, FEV(1)2) were obtained after inhalation of buffer solution (control) and 3 min after inhalation of aerosolized, serially diluted, histamine diphosphate solutions. A significant airways response (FEV1 decreasing by 20% or more from the control value) was observed in all subjects after inhalation of 5 mg/ml of histamine or less, indicating histamine airway hypersensitivity. At lower doses of histamine the mean values for FEV(1)1 and FEV(1)2 were similar to the control value. At higher histamine doses FEV(1)2 was consistently higher than FEV(1)1 (p = 0.007) and exceeded FEV1 1 by a mean of 9% after inhalation of the provocational histamine concentration; delta FEV1(FEV(1)2-FEV(1)1) was correlated with the log10 of cumulative inhaled histamine dose units (p = 0.040). Assuming that the difference between corresponding FEV1 determinations at a given level of induced bronchoconstriction is a direct consequence of changes in lung mechanics induced by deep inspiration, we are led to conclude that during histamine inhalation challenges, only 1 spirogram should be performed at each level of induced bronchoconstriction.     

Late airway responses to antigen challenge in sensitized inbred rats

We studied the magnitude and the time course of changes in pulmonary resistance (RL) after aerosol challenge with chicken ovalbumin (OA) of 15 sensitized, highly inbred Brown-Norway (BN) rats. Animals were actively sensitized and 2 wk later were challenged through the airways. Airway responses of sensitized animals were compared to those of 6 control animals challenged with sufficient methacholine (MCh) to at least double RL and to 4 unsensitized control rats challenged with OA. Ten of 15 rats in the experimental group displayed an early response (ER), defined as an increase in RL of at least 50% within 1 h of challenge. A late response (LR) was considered to have occurred when the value of RL exceeded the mean plus 2 standard deviations of all the measurements taken from 1 h after challenge to the end of the experiment. Two rats died less than 240 min after OA challenge with RL greater than 200% baseline. The remaining 13 were studied for a total duration that ranged from 390 to 720 min and of these animals 10 demonstrated LRs. Maximal RL during the LR after OA was 287 +/- 49% (SE) baseline (range, 129 to 760) versus 115 +/- 15% (75 to 176) for control animals after MCh (p less than 0.01) and 52 +/- 3% (51 to 142; p less than 0.01) for unsensitized control animals after OA. There was no correlation between the magnitude of ER and LR; 3 LRs occurred in the absence of detectable ERs. The median time to the peak of the LR was 450 min; median duration of LRs was 90 min (range, 30 to 135 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Large and small airway responses to bronchoconstrictors in the guinea pig and ferret

In the isolated, perfused lung lobe of the ferret we evaluated the bronchoconstrictor response of its airways to methacholine and histamine, pharmacologic agents associated with the asthmatic state. The bronchus of excised lobes was cannulated and needle scarifications were made on the pleural surface to allow perfusate to exit. Lung airways were perfused at constant flow with equilibrated 95% O2/5% CO2, warmed Krebs-Ringers solution. Perfusion pressure was measured as a gauge of airway resistance. A concentration-dependent smooth muscle contraction of the ferret lung lobes was observed to methacholine and histamine. The ED50's of methacholine and histamine were 6.41 x 10(-6) M +/- 1.38 x 10(-6) (SEM) and 6.41 x 10(-6) M +/- 1.38 x 10(-6) (SEM) and 2.39 x 10(-6) M +/- 0.53 x 10(-6) (SEM), respectively. The maximum level of bronchoconstriction developed in the ferret (2.42 mmHg/ml/min +/- 0.28 SEM (resistance units] in response to methacholine, was six times greater than that found for histamine (0.42 mmHg/ml/min +/- 0.05 SEM). Responses to both agonists were less pronounced in the ferret lung preparation than those in a similar lung preparation of guinea pig. Compliance changes in both animals were also evaluated. The ferret did not demonstrate a compliance change in response to histamine as was seen for methacholine, suggesting that resistance changes precede compliance changes, or that the ferret airways are particularly resistant to histamine. Despite a lesser contractile response, the ferret has the advantage of a relatively large lung and long trachea that allow study in several preparations obtained from a single animal. It should prove a useful animal model for study of pulmonary pharmacology.     

Nifedipine aerosol attenuates airway constriction in dogs with hyperreactive airways

We investigated the ability of a calcium channel blocker nifedipine, given as an aerosol, to attenuate bronchoconstriction induced by citric acid, Ascaris antigen, and methacholine in Basenji-Greyhound dogs. citric acid 10% increased pulmonary resistance (RL) 4.2-fold +/- 1.0 (mean +/- SEM) and 1.7-fold +/- 0.7 in untreated and nifedipine-pretreated dogs (P less than 0.05). Dynamic compliance (Cdyn) fell to 0.58 +/- 0.07 and 0.66 +/- 0.07 of control values in untreated and nifedipine-treated dogs, respectively (p greater than 0.05). Ascaris antigen increased RL 5.1-fold +/- 0.83 and 3-fold +/- 0.48 in untreated and nifedipine-treated dogs, respectively (p less than 0.05); Cdyn decreased to 0.33 +/- 0.04 and 0.48 +/- 0.03 in untreated and nifedipine-treated dogs, respectively (p less than 0.05). In 5 dogs challenged with 0.3 mg/ml methacholine, RL increased 6.1-fold +/- 0.7 and 4.4-fold +/- 1.0 in untreated and nifedipine-treated dogs, respectively (p less than 0.05); Cdyn fell to 0.41 +/- 0.-3 and 0.46 +/- 0.07 of control values in untreated and nifedipine-treated dogs (P greater than 0.05). Neither 40% ethanol nor nifedipine-ethanol altered resting RL and Cdyn. We conclude that nifedipine effectively attenuates bronchoconstriction induced by citric acid, Ascaris antigen, and methacholine in dogs with hyperreactive airways.     

Effect of bronchial thermoplasty on airway distensibility.

Recent studies have reported that the application of thermal energy delivered through a bronchoscope (bronchial thermoplasty) impairs the ability of airways to narrow in response to methacholine. How such altered smooth muscle affects the response of airways to lung inflation may have important clinical implications, particularly as it relates to the abnormal response of asthmatic subjects to lung inflation and deep inspiration. The aim of this study was to examine whether bronchial thermoplasty affected airway distension with lung inflation in relaxed and contracted airways. A total of 230 airways were studied, ranging 2.5-15 mm, in six dogs. These airways were divided into two groups: an untreated (control) population and a bronchial thermoplasty-treated population. Prior to treatment, the airway pressure-area curves in the two groups of airways were identical. In contrast, the relaxed and contracted airway pressure-area curves in treated airways were shifted upward at all points, showing increased airway area at both 3 and 5 weeks post-treatment. In conclusion, these results show that reducing that amount of functional smooth muscle with bronchial thermoplasty leads to increased airway size in both relaxed and contracted states over a normal range of inflation pressures.