Abstract

This proposal continues its focus on defining the mechanisms and receptors by which leukotriene E4 (LTE4), the most stable and abundant of the cysteinyl leukotrienes (cysLTs), promotes persistent airway inflammation and dysfunction. Using a combination of functional assays, biochemical approaches, newly created transgenic mouse strains, and two novel mouse models, we have begun to reveal the pathways by which LTE4 promotes airway eosinophilia and cytokine generation, and by which it induces bronchoconstriction. The central hypothesis of this application for renewal is that LTE4 elicits airway pathology by a hierarchical mechanism involving the activation of both mast cells (MCs) (directly through the novel LTE4 receptor GPR99 and platelets (indirectly through one or more MC products), the secondary generations of thromboxane A2 (TXA2), and prostaglandin D2 (PGD2), and stimulation of hematopoietic and non-hematopoietic T prostanoid (TP) receptors and chemoattractant homologous molecule expressed by Th2 cells (CRTH2) by these mediators, resulting in bronchoconstriction and amplification of inflammation.
Aim 1 will identify the receptors that mediate pulmonary responses to LTE4 and identify the mechanisms responsible for their dysregulation in airway inflammation.
Aim 2 will determine the respective contributions of MCs, platelets, and innate lymphoid type 2 cells (ILC2s) to the inflammatory and contractile effects of LTE4 in the airway.
Aim 3 will determine the role of MC- and platelet- derived prostaglandins (PGs) in conveying the airway responses to LTE4, and identify their sites of action. These studies are expected to uncover potential therapeutic targets for asthma that are not addressed by currently available antagonists.

Public Health Relevance

The experiments proposed in this application seek to determine how a chemical known as leukotriene E4 promotes the development and persistence of asthma. Successful completion of these studies should result in new approaches to the treatment of the disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078908-10
Application #
9681399
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Dong, Gang
Project Start
2009-07-17
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

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
Ordovas-Montanes, Jose; Dwyer, Daniel F; Nyquist, Sarah K et al. (2018) Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:649-654
Pan, Dingxin; Buchheit, Kathleen M; Samuchiwal, Sachin K et al. (2018) COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity. J Allergy Clin Immunol :
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

Showing the most recent 10 out of 33 publications