[Show abstract][Hide abstract] ABSTRACT: Mouse models of allergen provocation and/or transgenic gene expression have provided significant insights regarding the cellular, molecular, and immune responses linked to the pathologies occurring as a result of allergic respiratory inflammation. Nonetheless, the inability to replicate the eosinophil activities occurring in patients with asthma has limited their usefulness to understand the larger role(s) of eosinophils in disease pathologies. These limitations have led us to develop an allergen-naive double transgenic mouse model that expresses IL-5 systemically from mature T cells and eotaxin-2 locally from lung epithelial cells. We show that these mice develop several pulmonary pathologies representative of severe asthma, including structural remodeling events such as epithelial desquamation and mucus hypersecretion leading to airway obstruction, subepithelial fibrosis, airway smooth muscle hyperplasia, and pathophysiological changes exemplified by exacerbated methacholine-induced airway hyperresponsiveness. More importantly, and similar to human patients, the pulmonary pathologies observed are accompanied by extensive eosinophil degranulation. Genetic ablation of all eosinophils from this double transgenic model abolished the induced pulmonary pathologies, demonstrating that these pathologies are a consequence of one or more eosinophil effector functions.
Full-text · Article · Jul 2007 · The Journal of Immunology
[Show abstract][Hide abstract] ABSTRACT: RationaleThe refractory character of mouse eosinophils with respect to activation/degranulation has limited the utility of these animals as models of eosinophil effector functions (EEFs) in the lung and, therefore, human diseases. The effects of ectopic expression of both IL-5 and eotaxin-2 were assessed to develop a model system that duplicates the EEFs that occur in the lungs of asthma patients.
[Show abstract][Hide abstract] ABSTRACT: RationaleTissue eosinophilia is an accepted hallmark feature of parasite infections and allergen-mediated inflammatory responses. We have developed a number of polyclonal and monoclonal antibodies specific for mouse eosinophils and their associated products to facilitate studies of this leukocyte and the use of mouse models of human diseases.
[Show abstract][Hide abstract] ABSTRACT: Airway function in health and disease as well as in response to bronchospastic stimuli (i.e., irritants, allergens, and inflammatory mediators) is controlled, in part, by cholinergic muscarinic receptor regulation of smooth muscle. In particular, the dependence of airway smooth muscle contraction/relaxation on heterotrimeric G protein-coupled receptor signaling suggests that these events underlie the responses regulating airway function. Galphaq-containing G proteins are proposed to be a prominent signaling pathway, and the availability of knockout mice deficient of this subunit has allowed for an investigation of its potential role in airway function. Airway responses in Galphaq-deficient mice (activities assessed by both tracheal tension and in vivo lung function measurements) were attenuated relative to wild-type controls. Moreover, ovalbumin sensitization/aerosol challenge of Galphaq-deficient mice also failed to elicit an allergen-induced increase in airway reactivity to methacholine. These findings indicate that cholinergic receptor-mediated responses are dependent on Galphaq-mediated signaling events and identify Galphaq as a potential target of preventative/intervening therapies for lung dysfunction.
Full-text · Article · Aug 2003 · AJP Lung Cellular and Molecular Physiology