Concurrent dual allergen exposure and its effects on airway hyperresponsiveness, inflammation and remodeling

Asthma is a chronic disease of the respiratory tract, characterized by variable degrees of airflow obstruction, and is associated with airway inflammation, airway remodeling and airway hyperresponsiveness (AHR) (O’Byrne and Inman, 2003). The initiation and persistence of various aspects of asthma can often be attributed to exposure to one or more allergens (Pomes, 2002). Inhaled allergens are capable of inducing an inflammatory response in sensitized individuals and consequently cause, or exacerbate, respiratory symptoms that are characteristic of asthma (Wills-Karp, 1999). How allergens contribute to allergic sensitization and, in turn, airway inflammation and airway dysfunction remains unclear. An ongoing hypothesis is that the inflammatory response resulting from inhaled allergen might drive AHR directly, or induce structural changes in the airway leading to persistent AHR (Laprise et al., 1999; O’Byrne and Inman, 2003). Experimental mouse models of asthma have offered important insights into the mechanisms of allergen-induced asthma (Epstein, 2004; Hellings and Ceuppens, 2004; Taube et al., 2004). Our lab uses two mouse models of allergic asthma involving chronic exposure to either (1) ovalbumin (OVA), an innocuous antigen capable of inducing airway inflammation, airway remodeling and AHR, but only if administered systemically when conjugated with an aluminum-based adjuvant prior to intrapulmonary challenge (Kheradmand et al., 2002), or (2) house dust mite (HDM), a naturally occurring allergen that, when given via the airway, readily induces an asthmatic phenotype without the need for adjuvant or systemic sensitization. Both allergen exposure protocols result in immune-mediated airway inflammation defined by: elevated levels of IgE, the T-helper cell 2 (TH2) cytokines interleukin (IL)-4, -5 and -13, and eosinophils; airway remodeling defined by increases in airway smooth muscle, collagen deposition and goblet cell hyperplasia; and AHR that is sustained after the resolution of eosinophilic inflammation (Inman et al., 1999; Leigh et al., 2002; Leigh et al., 2004c; Leigh et al., 2004a; Leigh et al., 2004b; Southam et al., 2007). Most published models of allergic asthma typically explore responses to a single allergen. However, it is unlikely that humans are only exposed to a single allergen. In fact, natural exposure to a combination of two or more common aeroallergens has been linked with an increased risk for asthmatic symptoms (Gehring et al., 2001). This provokes the question: will concurrent exposure to more than one allergen in a mouse model worsen the asthmatic phenotype? The concept that the interaction between more than one allergen might lead to worsened disease is supported by a mouse model of brief allergen exposure (Sarpong et al., 2003), in which, compared with a single allergen, the combination of two allergens resulted in enhanced levels of airway inflammation and epithelial damage, but not airway reactivity. The sustained effects of concurrent exposure to multiple allergens in a chronic mouse model of asthma remain unknown. Given the central role that inflammation is believed to play in asthmatic pathophysiology, we RESEARCH ARTICLE