Aspirin-exacerbated respiratory disease (AERD) is a severe disorder characterized by asthma, recurrent nasal polyposis, and marked eosinophilic inflammation of the sinonasal and bronchial mucosa. It accounts for ~5% of asthma, and for a disproportionate share (~30%) of severe asthma. Therapeutic options are limited by a lack of understanding of disease pathogenesis. No suitable animal model has been reported to date. This proposal uses a novel mouse model of AERD to test the overriding hypothesis that AERD arises in hosts who are predisposed to abnormal function of any one of several interconnected control points of a lipid mediator hierarchy. These abnormalities result in failure of the prostaglandin (PG)E2-EP2 receptor system to control the synthesis and effector actions of cysteinyl leukotrienes (cys-LTs). A superimposed inflammatory insult results in markedly exaggerated eosinophilic respiratory tract inflammation with augmented downstream pathogenetic effects of the thromboxane A2 (TXA2)-T prostanoid (TP) receptor system as a final common pathway. We have found that house dust mite-treated ptges-/- mice (which lack the capacity to produce PGE2 through the inducible COX-2 enzyme), but not WT controls, bronchoconstrict when challenged by inhalation with inhaled lysine-aspirin (Lys-ASA), and generate ~3-fold higher quantities of cys-LTs than do WT controls. Remarkably, genetic deletion or pharmacologic blockade of TP receptors completely protect ptges-/- mice from bronchial eosinophilia, Th2 cytokine generation, and pulmonary ICAM-1 induction despite persistent high level pulmonary cys-LT production. We now seek to determine precisely how perturbations at individual control points in a lipid mediator hierarchy lead to the phenotype of AERD. Because our data suggest that TP receptors may be major therapeutic targets in AERD, we will also seek to identify the mechanism(s) that account for their functions. The studies proposed will reveal potential causative mechanisms in AERD and identify therapeutic targets that could restore normal homeostasis.
Aspirin-exacerbated respiratory disease (AERD) is a severe form of asthma that also involves difficult to control chronic sinusitis. Treatment options are limited, in part, because of a lack of understanding of its cause. The studies in this proposal wil uncover new potential treatments for AERD using a new experimental form of the disease in mice.
|Liu, Tao; Barrett, Nora A; Kanaoka, Yoshihide et al. (2018) Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity. J Immunol 200:915-927|
|Cahill, Katherine N; Katz, Howard R; Cui, Jing et al. (2017) KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 376:1911-1920|
|Samuchiwal, Sachin K; Balestrieri, Barbara; Raff, Hannah et al. (2017) Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway. J Biol Chem 292:8195-8206|
|Buchheit, Kathleen M; Cahill, Katherine N; Katz, Howard R et al. (2016) Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 137:1566-1576.e5|
|Kondeti, Vinay; Al-Azzam, Nosayba; Duah, Ernest et al. (2016) Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3. J Allergy Clin Immunol 137:289-298|
|Cahill, Katherine N; Raby, Benjamin A; Zhou, Xiaobo et al. (2016) Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease. Am J Respir Cell Mol Biol 54:34-40|
|Liu, Tao; Kanaoka, Yoshihide; Barrett, Nora A et al. (2015) Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway. J Immunol 195:3537-45|
|Boyce, Joshua A; Barrett, Nora A (2015) Cysteinyl leukotrienes: an innate system for epithelial control of airway smooth muscle proliferation? Am J Respir Crit Care Med 191:496-7|
|Liu, Tao; Garofalo, Denise; Feng, Chunli et al. (2015) Platelet-driven leukotriene C4-mediated airway inflammation in mice is aspirin-sensitive and depends on T prostanoid receptors. J Immunol 194:5061-8|
|Cahill, Katherine N; Bensko, Jillian C; Boyce, Joshua A et al. (2015) Prostaglandin D?: a dominant mediator of aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 135:245-52|
Showing the most recent 10 out of 22 publications