Chronic Airway Hyperreactivity, Goblet Cell Hyperplasia, and Peribronchial Fibrosis during Allergic Airway Disease Induced by Aspergillus fumigatus

Hogaboam, Cory M.; Blease, Kate; Mehrad, Borna; Steinhauser, Matthew L.; Standiford, Theodore J.; Kunkel, Steven L.; Lukacs, Nicholas W.

doi:10.1016/s0002-9440(10)64775-x

Cited by 170 publications

(236 citation statements)

References 37 publications

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“…An important finding of this study, however, was that repeated PFT recordings had no impact on leukocyte distributions in BAL samples among all groups of nonsensitized mice. This enabled us to show that airway hyperresponsiveness in A. fumigatus-treated mice was linked with pronounced eosinophilia and lymphocytosis in BAL (Table 2) (12). These results with BAL were supported by histopathological evaluation demonstrating that single and repeated PFT elicited only minor histological alterations of the proximal trachea and larynx in nonsensitized mice regardless of the number of PFT (Fig.…”

Section: Discussionsupporting

confidence: 61%

Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice

Glaab

Mitzner

Braun

et al. 2004

Journal of Applied Physiology

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Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice. J Appl Physiol 97: 1104 -1111, 2004. First published April 30, 2004 10.1152/japplphysiol.01182.2003.-Precise and repeatable measurements of pulmonary function in intact mice are becoming increasingly important for experimental investigations on various respiratory disorders including asthma. Here, we present validation of a novel in vivo method that, for the first time, combines direct and repetitive recordings of standard pulmonary mechanics with cholinergic aerosol challenges in anesthetized, orotracheally intubated, spontaneously breathing mice. We demonstrate that, in several groups of nonsensitized BALB/c mice, dose-related increases in pulmonary resistance and dynamic compliance to aerosolized methacholine are reproducible over short and extended intervals without causing detectable cytological alterations in the bronchoalveolar lavage or relevant histological changes in the proximal trachea and larynx regardless of the number of orotracheal intubations. Moreover, as further validation, we confirm that allergic mice, sensitized and challenged with Aspergillus fumigatus, were significantly more responsive to cholinergic challenge (P Ͻ 0.01) and exhibited marked eosinophilia and lymphocytosis in bronchoalveolar lavage fluids as well as significant pathological alterations in laryngotracheal histology compared with nonsensitized mice. We suggest that this approach will provide useful and necessary information on pulmonary mechanics in studies of various respiratory disorders in mice, including experimental models of asthma and chronic obstructive pulmonary disorder, investigations of pulmonary pharmacology, or more general investigations of the genetic determinants of lung function. experimental animal models; pulmonary function test; allergy; bronchial asthma THE ABILITY TO MEASURE PULMONARY FUNCTION in individual mice on repeated occasions is of great interest because of the prominent role played by these animals in genetic and translational research into the causes and mechanisms of respiratory and allergic diseases such as asthma (5,14). It is becoming increasingly evident that the real potential of gene-or cellbased applications in experimental asthma models is tightly linked to a solid understanding of the underlying respiratory pathophysiology (20). This growing interest in functional studies with mice that correlate in vitro findings with in vivo determination of respiratory physiology has prompted the search for measurements of pulmonary function that are valid and easy to implement.Existing methods for measuring respiratory function in mice in vivo include noninvasive and invasive technologies (2, 5). Noninvasive determination of airway responsiveness (AR) in intact conscious mice has gained much interdisciplinary interest as a convenient and effective method for screening respiratory function over extended periods of time (11).Concerns with existing noninvasive methods in spontaneously ...

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Section: Discussionsupporting

confidence: 61%

Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice

Glaab

Mitzner

Braun

et al. 2004

Journal of Applied Physiology

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“…instillation with live A. fumigatus conidia. 28 Prior approval for mouse use was obtained from the University Committee on Use and Care of Animals at the University of Michigan.…”

Section: Individual and Combination Cpg And Anti-st2l Mab Therapies Dmentioning

confidence: 99%

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

Ramaprakash

Shibata

Duffy³

et al. 2011

The American Journal of Pathology

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IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.

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“…Experimental protocols for airway allergen challenge in these models of airway disease involve three main routes of administration: (1) transnasal [4], (2) intratracheal [7], and Correspondence to: M Desco; e-mail: desco@mce.hggm.es (3) inhaled [11,12,18]. Our study focuses on transnasal administration.…”

Section: Introductionmentioning

confidence: 99%

Assessment of Airway Distribution of Transnasal Solutions in Mice by PET/CT Imaging

et al. 2009

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Purpose: Transnasal administration is one of the most common routes for allergen challenge in mouse models of airway diseases. Although this technique is widely used, neither the amount of allergen that reaches the lung nor its airway distribution has been well established. We used positron emission tomography (PET) and computed tomography (CT) to examine the anatomical distribution of a solution containing a tracer immediately after transnasal delivery and to determine the possible influence of age and administered volume. Procedures: Forty-six female BALB/c mice were divided into three groups according to instillation volume and age: (A) 15 μl, 8-10 weeks old (N=10), (B) 30 μl, 8-10 weeks old (N= 20), and (C) 30 μl, 32 weeks old (N=16). Anesthetized animals underwent a dynamic scan in a dedicated small-animal PET scanner immediately after transnasal administration of a solution containing 18 FDG. Regions of interest were used to obtain quantitative data. Animals were also imaged with a small-animal CT scanner to obtain complementary anatomical information. Results: Mean±SD (5.69±4.51%) of the solution administered reached the lungs in group A, 41.84±8.03% in group B, and 36.65±16.15% in group C. A comparable percentage was delivered to the left and right lungs in all the groups. Analysis of variance revealed a significant difference between the groups in the proportion of the solution that reached the lungs depending on the injection volume (PG0.001), but not depending on animal age. Conclusions: In this first report on quantitative imaging by PET and CT in small animals, we confirmed the suitability of the transnasal route with an instilled volume of 30 μl delivering fluids into the lower airways, although only about 40% of the dose reaches the lungs.

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Chronic Airway Hyperreactivity, Goblet Cell Hyperplasia, and Peribronchial Fibrosis during Allergic Airway Disease Induced by Aspergillus fumigatus

Cited by 170 publications

References 37 publications

Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice

Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

Assessment of Airway Distribution of Transnasal Solutions in Mice by PET/CT Imaging

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