Airway Hyperresponsiveness in Allergically Inflamed Mice

Abstract

Rationale: Allergically inflamed mice exhibit airway hyperresponsiveness to inhaled methacholine, which computer simulations of lung impedance suggest is due to enhanced lung derecruitment and which we sought to verify in the present study. Methods: BALB/c mice were sensitized and challenged with ovalbumin to induce allergic inflammation; the control mice were sensitized but received no challenge. The mice were then challenged with inhaled methacholine and respiratory system impedance tracked for the following 10 minutes. Respiratory elastance (H ) was estimated from each impedance measurement. One group of mice was ventilated with 100% O 2 during this procedure and another group was ventilated with air. After the procedure, the mice were killed and ventilated with pure N 2 , after which the trachea was tied off and the lungs were imaged with micro-computed tomography (micro-CT).Results: H was significantly higher in allergic mice than in control animals after methacholine challenge. The ratio of H at the end of the measurement period between allergic and nonallergic mice ventilated with O 2 was 1.36, indicating substantial derecruitment in the allergic animals. The ratio between lung volumes determined by micro-CT in the control and the allergic mice was also 1.36, indicative of a corresponding volume loss due to absorption atelectasis. Micro-CT images and histograms of Hounsfield units from the lungs also showed increased volume loss in the allergic mice compared with control animals after methacholine challenge. Conclusions: These results support the conclusion that airway closure is a major component of hyperresponsiveness in allergically inflamed mice.Keywords: asthma; micro-computed tomography; input impedance; lung derecruitment; lung volume Different mechanisms can lead to airway hyperresponsiveness (AHR) in animal models, not all of which have equal relevance to human asthma. It is therefore crucial to elucidate the mechanistic basis of AHR in any given animal model of asthma to understand its relationship to the human condition. We recently reported that the response of acutely allergically inflamed BALB/c mice to challenge with methacholine aerosol is likely due entirely to enhanced closure of peripheral airways secondary to increased (Received in original form October 3, 2006; accepted in final form January 25, 2007 ) Supported by NIH grants R01 HL67273 and NCRR-COBRE P20 RR15557.Correspondence and requests for reprints should be addressed to Lennart K. AT A GLANCE COMMENTARY Scientific Knowledge on the SubjectAirway hyperresponsiveness in mouse models of asthma has traditionally been attributed to contraction of airway smooth muscle. Recent studies suggest, however, that airway closure may play a more significant role. What This Study Adds to the FieldUsing the forced oscillation technique and micro-computed tomography, we now show that airway hyperresponsiveness in allergic mice can be largely explained by airway closure.airway mucosal thickness and secretions (1). This stands in marked contras...

Computational assessment of airway wall stiffness in vivo in allergically inflamed mouse models of asthma

“…With aerosol, H increases substantially, even in control animals, and in allergically inflamed mice the hyperresponsiveness in H is proportionally greater than that in either R or G, even when the fractional increases in R are not as great as in the present study (38). We have shown that these increases in H are due mainly to closure of small airways in the lung periphery (22,38). Interestingly, H was clearly somewhat elevated in the acutely inflamed animals (Fig.…”

“…To produce an acute inflammation, mice were sensitized with an intraperitoneal injection of ovalbumin (20 g in 2.25 mg alum) on days 0 and 14. They were challenged on each of days 21,22, and 23 by being placed in a compartmentalized aerosolization chamber and exposed to ovalbumin aerosol (1% in phosphate-buffered saline) for 30 min. Airway responsiveness to a bolus intravenous injection of 137 g/kg methacholine (0.074 mg/ml in ϳ40 l saline) was measured (see below) on day 25.…”

Evaluation of allergic lung inflammation by computed tomography in a rat modelin vivo

“…Two methods of volume segmentation, as described by others [1][2][3][4]13], were performed, in order to assess the advantages of and similarities between these methods. In Method 1, the thoracic volume was segmented by defining a region of interest that encapsulated the entire lung by manually outlining the ribcage and chest wall using characteristic landmarks and interpolation.…”

“…With respect to asthma, research utilising CT immediately following sacrifice, i.e. ex vivo, has elegantly contributed to establishment of the role of airway closure on hyperreactivity in mice undergoing acute allergic inflammation [4]. The ability to acquire CT data in a model of allergic asthma in vivo would be a step towards noninvasive assessment, utilising the same tools that are available in humans [5,6].…”

Airway segmentation and analysis for the study of mouse models of lung disease using micro-CT

“…The combination of micro-CT imaging and constant phase model parameters has also been used to analyze animal models of lung disease before. In particular, Lundblad et al (2007) qualitatively analyzed ex vivo micro-CT images in a mouse model of allergical inflammation and combined it with measurements of tissue elastance. In this work, we propose to use quantitative airway measurements since this approach is likely to provide valuable information to better understand the morphology and function of lungs affected by diseases such as emphysema and inflammation.…”