Indices Of Airway Responsiveness Research Articles

Airway Hyperresponsiveness in Asthma: A Better Understanding Yet to Yield Clinical Benefit

Airway inflammation and hyperresponsiveness (AHR) are important features of asthma. Both inflammation and AHR are complex traits that can each originate from a plethora of factors, where every factor can be independent, interconnected and dispensable. This review examines the complexity of the indices that we use to assess airway responsiveness. These indices entail intricate information regarding the individual and the combined dynamic behavior of all the airways that constitute the tracheobronchial tree during the activation of airway smooth muscle (ASM). Because many factors other than ASM contractility can influence airway narrowing, the defects responsible for the manifestation of AHR are difficult to infer. New tests and technologies are being developed to decipher the meaning of the indices of airway responsiveness and have already leaped forward our understanding of AHR. This review also gives prominence to the concept of ASM plasticity.ASM mass and contractile capacity is not fixed over time. Several facets of inflammation can increase ASM force indirectly over a prolong period of time by causing tissue damage and repair, which ultimately leads of airway wall remodeling that embodies an enlargement of ASM mass. This could contribute to the fixed component of AHR. The gain of force due to inflammation can also be transient and conditional to the presence of inflammatory mediators that are capable of increasing the contractile capacity of ASM. This could contribute to the variable, and more readily modifiable, component of AHR. We are now aware that a multitude of muscle and non-muscle factors can contribute to AHR within an asthmatic individual, and that these factors are often times distinct between individuals. Consequently, the relative contribution of a single factor within a group of patients is usually very small. This is the reason why our ever-growing understanding of AHR in asthma does not quite yet avail patients.

Differential effects of low and high-dose estradiol on airway reactivity in ovariectomized rats

The aim of this animal study was to test the hypothesis that low and high doses of 17beta-estradiol (E2) may differentially influence airway responsiveness. Ovariectomized female rats received either placebo or E2 (10 or 100 microg/kg per day) for 21 days. The concentration of inhaled acetylcholine (ACh) required to double pulmonary resistance (EC200 RL) was calculated as the in vivo index of airway responsiveness. Ex vivo airway responsiveness was evaluated by the cumulative concentration-response curve (CCRC) of isolated tracheal segments. Rats treated with low-dose E2 were less responsive to ACh than rats given either placebo or high-dose E2 (P=0.003). Ex vivo, low-dose E2 treatment decreased (P=0.01) and high-dose E2 increased the potency of ACh (P<0.001) compared to placebo. E2 treatment did not alter smooth muscle cross-sectional area or epithelium thickness. Accumulation of liquid within the tracheal mucosa was moderately enhanced by high-dose E2 treatment compared with animals given either placebo or low-dose E2 (P=0.03). We conclude that E2 treatment has differential, dose-dependent effects on airway responsiveness to acetylcholine.

Estradiol decreases the acetylcholine-elicited airway reactivity in ovariectomized rats through an increase in epithelial acetylcholinesterase activity.

Estrogen replacement therapy (ERT) is frequently prescribed for postmenopausal women. Epidemiological data suggest that sex hormones may play a role in the expression of asthma, but the mechanism(s) whereby this influence is mediated remain(s) unclear. To better understand the role of physiologic doses of estrogens in airway function, we tested the hypothesis that 17beta-estradiol (E(2), 10 microg/kg per d for 21 d) given to oophorectomized female rats modifies airway responsiveness to cholinergic agonists, compared with oophorectomized rats given placebo. In vivo, the concentration of inhaled acetylcholine (ACh) required to double pulmonary resistance (EC(200)RL) in anesthetized spontaneously breathing tracheotomized rats was calculated as an index of airway responsiveness. E(2)-treated rats were less responsive to ACh than placebo-treated rats (EC(200)RL, 9.40 +/- 1.48 vs. 1.52 +/- 0.85 mg. ml(-1), respectively). Ex vivo airway responsiveness was evaluated with the cumulative concentration-response curve (CCRC) of isolated tracheal segments. Compared with placebo, E(2) treatment significantly increased the EC(50) of ACh (p = 0.01) but did not alter the CCRC to carbachol. Removing the epithelium or treatment with physostigmine abolished the difference in EC(50) of ACh between the groups. Acetylcholinesterase (AChE) activity of homogenized whole trachea was 1.4-fold greater in the E(2)-treated group compared with placebo (p = 0.02), whereas no difference was found in homogenized epithelium-free trachea. We conclude that E(2) treatment decreases airway responsiveness to ACh in ovariectomized rats at least in part by increasing AChE activity dependent on the presence of the epithelium.

Airway responsiveness to methacholine, respiratory symptoms, and dust exposure levels in grain and flour mill workers in eastern france

Our goal was to assess the relation between dust exposure levels and the respiratory health status of workers in grain and flour mills in eastern France. We studied 118 male workers from 11 mills and 164 unexposed male controls. Dust concentration was measured by personal sampling methods. Outcome variables included respiratory symptoms, routine pulmonary function tests, and indices of airway responsiveness to methacholine. A great within- and between-area variability of inhalable dust concentration was found in all mills. A dose-response relationship was observed between dust exposure levels and chronic respiratory symptoms, suggesting that exposure to grain and flour dust may lead to chronic bronchitis. A significant relation was found between dust exposure and airway hyper-responsiveness; this finding is important since it has been hypothesized that the latter abnormality may lead to or be a predisposing factor in subsequent chronic, irreversible airflow obstruction.

Respiratory responses to repeated prolonged exposure to 0.12 ppm ozone.

Repeated exposure to high concentrations of ozone results first in augmentation (typically on the second day) and then attenuation of pulmonary response in humans. To determine the effects of repeated prolonged low-concentration ozone exposure, we exposed 17 healthy nonsmoking male subjects to 0.12 ppm ozone for 6.6 h on 5 consecutive days. Subjects were also exposed once to filtered air. Volunteers exercised at a ventilation of approximately 39 L/min for 50 min of each hour during the exposure. Spirometry, plethysmography, and symptom responses were obtained before, during, and after each exposure. Nasal lavage and aerosol bolus dispersion were obtained before and after exposure. Spirometry decreased and symptoms increased on the first day. Responses were less on the second day compared with those on the first day, and they were absent compared with control values on the subsequent 3 days of ozone exposure. Percent change in FEV1 after ozone exposure compared with that after air exposure averaged -12.79, -8.73, -2.54, -0.6, +0.18% for Days 1 to 5 of ozone exposure, respectively. FEV1 responses ranged from a zero to 34% decrease on Days 1 and 2. After each exposure, we determined the ratio of SRaw after inhaling a fixed dose of methacholine to SRaw after inhaling saline aerosol, as an index of airway responsiveness. Airway responsiveness was significantly increased after each ozone exposure. The mean ratios were 2.22, 3.67, 4.55, 3.99, 3.24, and 3.74 for filtered air and ozone Days 1 to 5, respectively. Symptoms of cough and pain on deep inspiration increased significantly on ozone Day 1 only.(ABSTRACT TRUNCATED AT 250 WORDS)

Increase in airway responsiveness and effect of deep inhalation on airway caliber in allergen-induced asthma. Relationship to the late-phase response.

The airway responsiveness to methacholine (MCh) and the effect of deep inhalation (DI) on airway caliber were determined in 18 asthmatic patients at baseline and 3 and 24 h after an allergen inhalation challenge. The dose of MCh causing a 20% fall of FEV1 (PD20) was used as an index of airway responsiveness; the ratio of forced expiratory flow at 40% of FVC from maximal and partial flow/volume curves (MEF40M/P) was used to assess the effect of DI on airway caliber. Thirteen patients showed a dual asthmatic response (DAR) to allergen, 5 patients an isolated early-phase asthmatic response (EAR). In the DAR patients, 3 h after allergen challenge, when the early-phase response had resolved and the late-phase response had yet to develop, MChPD20 (geometric mean) was reduced from 202 to 71 micrograms (P less than 0.001) whereas MEF40M/P at the MCh end point was unchanged (p greater than 0.4). Twenty-four hours after allergen challenge, when late-phase response had developed, MChPD20 was further reduced to 51 micrograms (p less than 0.02), and this reduction was accompanied by a decrease of MEF40M/P at the MCh end point (p less than 0.01). In the EAR patients, neither MChPD20 nor MEF40M/P was significantly changed at any time during the study. We conclude that most of the increase in airway responsiveness that follows acute exposure to allergen precedes the late-phase response and is not determined by the same mechanisms that impair the ability of the lung to dilate airways with a DI.(ABSTRACT TRUNCATED AT 250 WORDS)

Strain-related Differences in Airway Smooth Muscle and Airway Responsiveness in the Rat

The purpose of this study was to evaluate the possible role of the quantity of airway smooth muscle (AWSM) as a determinant of differences in responsiveness between inbred rat strains. To do this, we studied several batches of 8- to 10-wk-old Lewis and Fisher 344 rats. Animals were anesthetized intraperitoneally with pentobarbital (30 mg/kg) and xylazine (7 mg/kg). The peak value of pulmonary resistance (RL) was measured after progressively doubling concentrations of inhaled aerosolized methacholine (MCh). The MCh concentration required to double RL (EC200RL) was calculated as an index of airway responsiveness. Fisher rats were significantly more responsive than Lewis, and the interstrain variability in responsiveness was significantly greater than the intrastrain variability. Additional animals from the less responsive Lewis strain (n = 8) and the more responsive F344 strain (n = 11) were killed immediately after measurement of responsiveness, and AWSM was quantitated as a fraction of total lung tissue using a point-counting technique. F344 rats were again significantly more responsive than Lewis rats (EC200RL geometric mean: 0.72 versus 2.16 mg/ml, p less than 0.005). F344 rats also had significantly more AWSM than did Lewis rats (3.22 +/- 0.176 versus 2.48 +/- 0.185%, mean +/- SE, p less than 0.001). We conclude that highly inbred Fisher rat strains characteristically exhibit a degree of airways responsiveness greater than that of the Lewis strain and that the quantity of AWSM may be an important determinant of interstrain differences.

The dose-response slope: a useful method for expressing the results of methacholine provocation tests in healthy subjects?

In order to study the reproducibility of different indices of airway responsiveness, two bronchial provocations with increasing methacholine concentrations up to 256 mg ml-1 were performed within 2 weeks on 30 healthy volunteers. The dose-response slope [DRS = maximal fall (%) in pulmonary function/maximal non-cumulative methacholine dose (mumol)] was calculated from forced expiratory volume in 1 s (FEV1) and from area under the expiratory flow-volume curve (AEFV). DRS reproducibility within 2 weeks in responsive (decline in FEV1 greater than 20%) and non-responsive subjects (decline in FEV1 less than 20%) was assessed. After log-transformation of the data the reproducibility was assessed with intraclass correlations (ICC) [with 95% confidence intervals (CIicc)], mean difference with limits of agreement (delta +/- SD), 95% confidence intervals for a single measurement (CIsm), and the absolute difference of the observations of the two days from each other (zero = ideal reproducibility). Provocative doses (PD20FEV1) could be calculated for 14 subjects on both occasions. In this responsive group the reproducibility of all the parameters used (PD20FEV1, DRSFEV1 and DRSAEFV) was high. In the non-responsive group, DRSFEV1 demonstrated a slightly, but not clearly, lower ICC than DRSAEFV. However, DRSFEV1 had clearly wider limits of agreement and CIsm than DRSAEFV. Also, with DRSFEV1 the observations of the two days differed significantly more from each other than with DRSAEFV (P less than 0.05).

Assessment of Airway Responsiveness in Infants with Cystic Fibrosis

We compared the responses of cystic fibrosis (CF) (N = 14) and normal (N = 14) infants with inhaled methacholine. Airway function was assessed by forced expiratory flows at functional residual capacity (Vmax FRC) generated by the rapid compression technique, and methacholine responsiveness was quantitated as (1) TC: the threshold concentration to decrease Vmax FRC by 2 SD from baseline; (2) PC50: the provocative concentration to decrease Vmax FRC by 30%; and (3) SPC30; the slope of the dose-response curve between TC and PC30. There were no significant differences in age between CF and normal infants (16 +/- 8 versus 17 +/- 5 months, p greater than 0.3); however, the CF infants were shorter (74 +/- 10 versus 81 +/- 5 cm, p less than 0.05), had lower absolute Vmax FRC (241 +/- 103 versus 374 +/- 113 ml/s, p less than 0.001), and tended to have lower percentage of predicted flow values (87 +/- 13 versus 111 +/- 34%, p less than 0.10). Comparison of the indices of airway responsiveness revealed no difference in logTC; however, the CF infants had smaller, more negative values for logPC30 (-0.76 +/- 0.52 versus -0.22 +/- 0.53, p less than 0.02) and steeper slopes to their dose-response curves (logSPC30, 2.42 +/- 0.45 versus 1.88 +/- 0.74, p less than 0.025). Indices of airway responsiveness correlated significantly with baseline Vmax FRC (% of predicted). After the influence of baseline flow upon airway responsiveness was accounted for by multiple linear regression analysis, there was a tendency for CF infants to be more responsive than control infants.(ABSTRACT TRUNCATED AT 250 WORDS)