Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle.Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma, e.g. exercise-induced bronchoconstriction, evaluation before scuba diving.Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges, e.g. hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.
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.
We measured the changes in upper and lower airway resistance after inhalation of aerosols of methacholine (MCh) in doubling concentrations (16, 32, 64, and 128 mg/ml) in 11 anesthetized nonintubated spontaneously breathing rats. Upper airway resistance (Ru) increased from a control value of 0.48 +/- 0.04 cmH2O X ml-1 X s (mean +/- SE) to 0.85 +/- 0.15 after 128 mg/ml MCh, whereas lower airway resistance (Rlo) increased from 0.11 +/- 0.03 to 0.21 +/- 0.04. However, there was no correlation between the magnitudes of the changes in Ru and Rlo. In a further seven anesthetized spontaneously breathing rats aerosols of MCh were delivered into the lower airways via a tracheostomy and resulted in increases in Rlo from a control value of 0.20 +/- 0.03 to 0.66 +/- 0.12 after 128 mg/ml MCh. Ru also increased to approximately double its control value. We conclude that inhaled MCh causes narrowing of both Ru and Rlo in the anesthetized rat, the changes in Ru and Rlo are not correlated, and changes in Ru can occur when MCh deposition occurs only in the lower airways.
Treatment goals in asthma patients are the achievement of a good control of symptoms and the reduction of the risk of exacerbation. However, a "one-size-fits-all" therapeutic strategy is no longer appropriate to effectively pursue these goals, due to the heterogeneity of asthma. To make the treatment scenario even more complex, asthma patients often present comorbidities that may alter response to therapy. In addition, adherence to asthma treatment is poor. Given this complex and heterogeneous picture, the management of asthma is highly challenging. A clear diagnostic-therapeutic model of patients' care and the definition of the specific responsibilities of different healthcare providers appear necessary to improve clinical outcomes and better allocate healthcare resources. We present here a proposal for this model.
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.
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