This grant will investigate the pro-inflammatory feedback reaction that develops between interleukin (IL)-4 (and other cytokines) and cysteinyl leukotrienes (CysLTs) that leads to the inflammation, hyperplasia, and airway remodeling observed in chronic hyperplastic eosinophilic sinusitis (CHES) and asprin-exacerbated respiratory disease (AERD). AERD is a syndrome characterized by severe persistent asthma, aggressive airway remodeling, extensive hyperplastic eosinophilic sinusitis with nasal polyp (NP) formation, and intolerance to aspirin. Eosinophils are essential to the fibrotic processes associated with asthma and CHES. Aspirin intolerance reflects increased expression of leukotriene C4 synthase (LTC4S) and CysLT receptor expression and, as a result, these subjects have constitutive overproduction and heightened responsiveness to CysLTs. CysLTs function through their ability to interact with two homologous receptors: CysLTI and CysLT2 both of which are highly upregulated in AERD. We hypothesize that CysLTs contribute to the hyperplasia, fibrosis, and remodeling of AERD through their activation of eosinophils. Both the pathway responsible for CysLT synthesis and the expression of CysLT receptors are tightly regulated by cytokines, including prominently, IL-4. This pro-inflammatory feedback between CysLTs and IL-4 promotes eosinophil- mediated inflammation, mucus gland secretion, and the proliferation of airway smooth muscle, epithelium, and endothelium, leading to fibrosis.
In specific aim #1 we will dissect individual roles for CysLTI and CysLT2 receptors in these processes. Our hypothesis is that whereas the CysLTI receptor may be uniquely involved in bronchospasm, the upregulation of CysLT2 receptor-dependent pathways has more important remodeling functions in CHES/AERD.
Specific aim #2 will investigate the regulation of CysLT receptors and LTC4S expression by IL-4. Finally, aspirin desensitization is an effective treatment for AERD. Therefore specific aim #3 will investigate the role of IL-4 antagonism by aspirin as the therapeutic basis for the efficacy of this procedure
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|Steinke, John W; Smith, Anna R; Carpenter, Delaney J et al. (2017) Lack of Efficacy of Symptoms and Medical History in Distinguishing the Degree of Eosinophilia in Nasal Polyps. J Allergy Clin Immunol Pract 5:1582-1588.e3|
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|Steinke, John W; Borish, Larry (2016) Immune Responses in Rhinovirus-Induced Asthma Exacerbations. Curr Allergy Asthma Rep 16:78|
|Lal, Devyani; Jategaonkar, Ameya A; Borish, Larry et al. (2016) Management of rhinosinusitis during pregnancy: systematic review and expert panel recommendations. Rhinology 54:99-104|
|Kennedy, Joshua L; Steinke, John W; Liu, Lixia et al. (2016) Failure of itraconazole to prevent T-helper type 2 cell immune deviation: Implications for chronic rhinosinusitis. Am J Rhinol Allergy 30:379-384|
|Palacios, Thamiris; Stillman, Leland; Borish, Larry et al. (2016) Lack of basophil CD203c-upregulating activity as an immunological marker to predict response to treatment with omalizumab in patients with symptomatic chronic urticaria. J Allergy Clin Immunol Pract 4:529-30|
|Borish, Larry (2016) Rethinking chronic rhinosinusitis phenotypes. J Allergy Clin Immunol 138:1354-1355|
|Steinke, John W; Payne, Spencer C; Borish, Larry (2016) Eosinophils and Mast Cells in Aspirin-Exacerbated Respiratory Disease. Immunol Allergy Clin North Am 36:719-734|
|Lawrence, Monica G; Steinke, John W; Borish, Larry (2016) Basic science for the clinician: Mechanisms of sublingual and subcutaneous immunotherapy. Ann Allergy Asthma Immunol 117:138-42|
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