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RGS4 promotes allergen- and aspirin-associated airway hyperresponsiveness by inhibiting PGE2 biosynthesis.

Authors
  • Wong, Gordon S1
  • Redes, Jamie L1
  • Balenga, Nariman1
  • McCullough, Morgan1
  • Fuentes, Nathalie1
  • Gokhale, Ameya2
  • Koziol-White, Cynthia3
  • Jude, Joseph A3
  • Madigan, Laura A1
  • Chan, Eunice C1
  • Jester, William H3
  • Biardel, Sabrina4
  • Flamand, Nicolas4
  • Panettieri, Reynold A Jr3
  • Druey, Kirk M5
  • 1 Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH), Bethesda, Md.
  • 2 Food Allergy Research Unit, Laboratory of Allergic Diseases, NIAID/NIH, Bethesda, Md.
  • 3 Rutgers Institute for Translational Medicine and Science, Child Health Institute of New Jersey, Rutgers University School of Medicine, New Brunswick, NJ. , (Jersey)
  • 4 Centre de recherche de l'IUCPQ, Département de médecine, Faculté de médecine, Université Laval, Québec, Canada. , (Canada)
  • 5 Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH), Bethesda, Md. Electronic address: [email protected]
Type
Published Article
Journal
The Journal of allergy and clinical immunology
Publication Date
Nov 01, 2020
Volume
146
Issue
5
Identifiers
DOI: 10.1016/j.jaci.2020.03.004
PMID: 32199913
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Allergens elicit host production of mediators acting on G-protein-coupled receptors to regulate airway tone. Among these is prostaglandin E2 (PGE2), which, in addition to its role as a bronchodilator, has anti-inflammatory actions. Some patients with asthma develop bronchospasm after the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs, a disorder termed aspirin-exacerbated respiratory disease. This condition may result in part from abnormal dependence on the bronchoprotective actions of PGE2. We sought to understand the functions of regulator of G protein signaling 4 (RGS4), a cytoplasmic protein expressed in airway smooth muscle and bronchial epithelium that regulates the activity of G-protein-coupled receptors, in asthma. We examined RGS4 expression in human lung biopsies by immunohistochemistry. We assessed airways hyperresponsiveness (AHR) and lung inflammation in germline and airway smooth muscle-specific Rgs4-/- mice and in mice treated with an RGS4 antagonist after challenge with Aspergillus fumigatus. We examined the role of RGS4 in nonsteroidal anti-inflammatory drug-associated bronchoconstriction by challenging aspirin-exacerbated respiratory disease-like (ptges1-/-) mice with aspirin. RGS4 expression in respiratory epithelium is increased in subjects with severe asthma. Allergen-induced AHR was unexpectedly diminished in Rgs4-/- mice, a finding associated with increased airway PGE2 levels. RGS4 modulated allergen-induced PGE2 secretion in human bronchial epithelial cells and prostanoid-dependent bronchodilation. The RGS4 antagonist CCG203769 attenuated AHR induced by allergen or aspirin challenge of wild-type or ptges1-/- mice, respectively, in association with increased airway PGE2 levels. RGS4 may contribute to the development of AHR by reducing airway PGE2 biosynthesis in allergen- and aspirin-induced asthma. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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