Abstract
ABSTRACTHouse dust mite (HDM) challenge is commonly used in murine models of allergic asthma for preclinical pathophysiological studies. However, few studies define objective readouts or biomarkers in this model. In this study we characterized immune responses and defined molecular markers that are specifically altered after HDM challenge. In this murine model, we used repeated HDM challenge for two weeks which induced hallmarks of allergic asthma seen in humans, including airway hyper-responsiveness (AHR) and elevated levels of circulating total and HDM-specific IgE and IgG1. Kinetic studies showed that at least 24 h after last HDM challenge results in significant AHR along with eosinophil infiltration in the lungs. Histologic assessment of lung revealed increased epithelial thickness and goblet cell hyperplasia, in the absence of airway wall collagen deposition, suggesting ongoing tissue repair concomitant with acute allergic lung inflammation. Thus, this model may be suitable to delineate airway inflammation processes that precede airway remodeling and development of fixed airway obstruction. We observed that a panel of cytokines e.g. IFN-γ, IL-1β, IL-4, IL-5, IL-6, KC, TNF-α, IL-13, IL-33, MDC and TARC were elevated in lung tissue and bronchoalveolar fluid, indicating local lung inflammation. However, levels of these cytokines remained unchanged in serum, reflecting lack of systemic inflammation in this model. Based on these findings, we further monitored the expression of 84 selected genes in lung tissues by quantitative real-time PCR array, and identified 31 mRNAs that were significantly up-regulated in lung tissue from HDM-challenged mice. These included genes associated with human asthma (e.g. clca3, ear11, il-13, il-13ra2, il-10, il-21, arg1 and chia1) and leukocyte recruitment in the lungs (e.g. ccl11, ccl12 and ccl24). This study describes a biosignature to enable broad and systematic interrogation of molecular mechanisms and intervention strategies for airway inflammation pertinent to allergic asthma that precedes and possibly potentiates airway remodeling and fibrosis.
Highlights
Allergic asthma is a common chronic inflammatory lung disease, affecting nearly 300 million people worldwide, with significant health, health service and economic burden
In the last decade, House dust mite (HDM)-challenged murine models have been used to dissect different aspects of the pathogenesis and to begin to define some of the molecular mechanisms that may be important in the disease process of allergic asthma (Stevenson and Birrell, 2011). These models involves the sensitization of the animal to HDM by repeated intranasal challenge which results in a Th2-polarized bronchial inflammation, airway remodeling and epithelial damage similar to that seen in human asthma (Cates et al, 2004, 2007; Johnson et al, 2004)
Kinetics of cellular infiltration in the bronchoalveolar lavage fluid (BALF) following HDM challenge To assess the kinetics of lung inflammation, BALF samples collected 8, 24, 48 and 72 h after the last HDM challenge were used for cell differential analyses
Summary
Allergic asthma is a common chronic inflammatory lung disease, affecting nearly 300 million people worldwide, with significant health, health service and economic burden (www.publichealth. gc.ca). Allergic asthma is a common chronic inflammatory lung disease, affecting nearly 300 million people worldwide, with significant health, health service and economic burden As asthma is a heterogenous disorder with different subphenotypes (e.g. Th2-High vs Th2-Low; Woodruff et al, 2009), there are no therapies that are effective in all asthma patients. This has contributed to there being rather modest progress in developing new therapies that have a broad impact. Animal models of human asthma have not been extensively characterized using a Systems Biology approach, which has created a knowledge gap that has greatly limited success in promoting development of new therapies
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