Abstract
The relative contributions of large and small airways to hyperresponsiveness in asthma have yet to be fully assessed. This study used a mouse model of chronic allergic airways disease to induce inflammation and remodelling and determine whether in vivo hyperresponsiveness to methacholine is consistent with in vitro reactivity of trachea and small airways. Balb/C mice were sensitised (days 0, 14) and challenged (3 times/week, 6 weeks) with ovalbumin. Airway reactivity was compared with saline-challenged controls in vivo assessing whole lung resistance, and in vitro measuring the force of tracheal contraction and the magnitude/rate of small airway narrowing within lung slices. Increased airway inflammation, epithelial remodelling and fibrosis were evident following allergen challenge. In vivo hyperresponsiveness to methacholine was maintained in isolated trachea. In contrast, methacholine induced slower narrowing, with reduced potency in small airways compared to controls. In vitro incubation with IL-1/TNFα did not alter reactivity. The hyporesponsiveness to methacholine in small airways within lung slices following chronic ovalbumin challenge was unexpected, given hyperresponsiveness to the same agonist both in vivo and in vitro in tracheal preparations. This finding may reflect the altered interactions of small airways with surrounding parenchymal tissue after allergen challenge to oppose airway narrowing and closure.
Highlights
Asthma is characterized by inflammation, airway wall remodelling and airway hyperresponsiveness (AHR), whereby airways are more sensitive to a variety of stimuli and subsequently contract too and too much [1]
AHR to MCh was established in vivo in a mouse model of chronic airway disease (AAD) and maintained in measurements of force in tracheal ring preparations in vitro
Small airway narrowing in response to MCh measured in perfused lung slices from the same model was reduced following allergen challenge
Summary
Asthma is characterized by inflammation, airway wall remodelling and airway hyperresponsiveness (AHR), whereby airways are more sensitive to a variety of stimuli and subsequently contract too and too much [1]. Various animal models of allergic airway disease (AAD) have been used to elucidate mechanisms underlying the development of AHR following chronic allergen challenge [7] The majority of these studies have demonstrated AHR by assessing whole lung responses in vivo and/or the development of force in conveniently accessible large airways in organ bath studies under isometric conditions in vitro [8,9,10]. The use of lung slices, in which intact small airways maintain cell-cell and cell-matrix interactions with surrounding parenchyma, provides a physiologically relevant in vitro setting in which to explore the influence of allergen on small airway reactivity [11,12,13,14] Using this approach, a single study using a chronic ovalbumin (OVA) challenge model has reported that small airway responsiveness to a single maximally effective concentration of acetylcholine (ACh) was unchanged, despite airway remodelling and in vivo AHR to methacholine (MCh) [14]. This may require ex vivo incubation of lung slices with inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor a (TNFa), which have previously been demonstrated to induce AHR in tracheal preparations in vitro [15,16]
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