Assessment of Peripheral Airway Function following Chronic Allergen Challenge in a Sheep Model of Asthma

Abstract

BackgroundThere is increasing evidence that the small airways contribute significantly to the pathophysiology of asthma. However, due to the difficulty in accessing distal lung regions in clinical settings, functional changes in the peripheral airways are often overlooked in studies of asthmatic patients. The aim of the current study was to characterize progressive changes in small airway function in sheep repeatedly challenged with house dust mite (HDM) allergen.Methodology/Principal FindingsFour spatially separate lung segments were utilized for HDM challenges. The right apical, right medial, right caudal and left caudal lung segments received 0, 8, 16 and 24 weekly challenges with HDM respectively. A wedged-bronchoscope technique was used to assess changes in peripheral resistance (Rp) at rest, and in response to specific and non-specific stimuli throughout the trial. Allergen induced inflammatory cell infiltration into bronchoalveolar lavage and increases in Rp in response to HDM and methacholine were localized to treated lung segments, with no changes observed in adjacent lung segments. The acute response to HDM was variable between sheep, and was significantly correlated to airway responsiveness to methacholine (rs = 0.095, P<0.01). There was no correlation between resting Rp and the number of weeks of HDM exposure. Nor was there a correlation between the magnitude of early-phase airway response and the number of HDM-challenges.ConclusionsOur findings indicate that airway responses to allergic and non-allergic stimuli are localized to specific treated areas of the lung. Furthermore, while there was a decline in peripheral airway function with HDM exposure, this decrease was not correlated with the length of allergen challenge.

A novel segmental challenge model for bleomycin-induced pulmonary fibrosis in sheep

“…Functional changes in the different segments were measured in awake, consciously breathing sheep using a wedged-bronchoscope technique as previously described [13,21]. Using this procedure, we have verified that responses are localized within individual segments by our earlier studies utilizing sheep [13,21].…”

“…The segmental challenge approach involves administering bleomycin to spatially separate lung segments in a similar manner to that previously described by our group for infusing house dust mite to specific lung segments to model chronic asthma [11][12][13]. We and other groups using different experimental agents [14,15], have found that the segmental instillation approach limits the treatment effects to defined areas of the lung without any associated adverse systemic or overall clinical effects.…”

Increased vascular density is a persistent feature of airway remodeling in a sheep model of chronic asthma

“…A fibre-optic bronchoscope was used for localized delivery of solubilized HDM (1 mg in 5 mL phosphate buffered saline; PBS) into spatially separate lung segments. Previous studies have shown that both functional changes and inflammatory cell infiltration following a bolus HDM-challenge are localized to the specifically treated lung segment [17]. All experimental animal procedures and the collection of tissues were approved by the Animal Experimentation Ethics Committee of the University of Melbourne.…”

“…To investigate progressive stages of vascular remodeling, we studied archived airway tissue collected from the right apical, right medial, right caudal, and left caudal lung segments that were challenged weekly with HDM for different durations [17]. The commencement of challenges in each segment was staggered so that the right apical, right medial, right caudal, and left caudal segments received 0, 8, 16, or 24 weekly challenges respectively (n = 7).…”

“…Segmental lung function indices were taken from a separate study performed on these sheep [17] and used to ascertain whether the vascular remodeling found in this model was associated with lung function decline.…”