Liliana Machado-Carvalho1, Margarita Martín2, Rosa Torres3, Marta Gabasa4, Isam Alobid5, Joaquim Mullol5, Laura Pujols4, Jordi Roca-Ferrer4, Cesar Picado6. 1. Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: lsmachad@clinic.ub.es. 2. Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Biochemistry Unit, School of Medicine, Universitat de Barcelona, Barcelona, Spain. 3. Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Department of Pharmacology, Universitat Autònoma de Barcelona, Barcelona, Spain. 4. Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain. 5. Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Rhinology Unit & Smell Clinic, ENT Department, Hospital Clínic, Barcelona, Spain. 6. Clinical and Experimental Respiratory Immunoallergy, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Pneumology and Respiratory Allergy Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
Abstract
BACKGROUND: We hypothesized that the 2 reported alterations in aspirin-exacerbated respiratory disease (AERD), reduced expression/production of COX-2/prostaglandin (PG) E2 and diminished expression of E-prostanoid (EP) 2 receptor, are closely linked. OBJECTIVE: We sought to determine the mechanisms involved in the altered regulation of the COX pathway in patients with AERD. METHODS: Fibroblasts were obtained from nasal mucosa; samples of control subjects (NM-C, n = 8) and from nasal polyps from patients with aspirin-exacerbated respiratory disease (NP-AERD, n = 8). Expression of the autocrine loop components regulating PGE2 production and signaling, namely IL-1 type I receptor (IL-1RI), COX-2, microsomal prostaglandin E synthase 1 (mPGES-1), and EP receptors, was assessed at baseline and after stimulation with IL-1β, PGE2, and specific EP receptor agonists. RESULTS: Compared with NM-C fibroblasts, basal expression levels of IL-1RI and EP2 receptor were lower in NP-AERD fibroblasts. IL-1β-induced IL-1RI, COX-2, and mPGES-1 expression levels were also lower in these cells. Levels of IL-1RI positively correlated with COX-2 and mPGES-1 expression in both NM-C and NP-AERD fibroblasts. Incubation with either exogenous PGE2 or selective EP2 agonist significantly increased expression of IL-1RI in NM-C fibroblasts and had hardly any effect on NP-AERD fibroblasts. Alterations in IL-1RI, COX-2, and mPGES-1 expression that were found in NP-AERD fibroblasts were corrected when EP2 receptor expression was normalized by transfection of NP-AERD fibroblasts. CONCLUSION: Altered expression of EP2 in patients with AERD contributes to deficient induction of IL-1RI, reducing the capacity of IL-1β to increase COX-2 and mPGES-1 expression, which results in low PGE2 production. This impairment in the generation of PGE2 subsequently reduces its ability to induce IL-1RI.
BACKGROUND: We hypothesized that the 2 reported alterations in aspirin-exacerbated respiratory disease (AERD), reduced expression/production of COX-2/prostaglandin (PG) E2 and diminished expression of E-prostanoid (EP) 2 receptor, are closely linked. OBJECTIVE: We sought to determine the mechanisms involved in the altered regulation of the COX pathway in patients with AERD. METHODS: Fibroblasts were obtained from nasal mucosa; samples of control subjects (NM-C, n = 8) and from nasal polyps from patients with aspirin-exacerbated respiratory disease (NP-AERD, n = 8). Expression of the autocrine loop components regulating PGE2 production and signaling, namely IL-1 type I receptor (IL-1RI), COX-2, microsomal prostaglandin E synthase 1 (mPGES-1), and EP receptors, was assessed at baseline and after stimulation with IL-1β, PGE2, and specific EP receptor agonists. RESULTS: Compared with NM-C fibroblasts, basal expression levels of IL-1RI and EP2 receptor were lower in NP-AERD fibroblasts. IL-1β-induced IL-1RI, COX-2, and mPGES-1 expression levels were also lower in these cells. Levels of IL-1RI positively correlated with COX-2 and mPGES-1 expression in both NM-C and NP-AERD fibroblasts. Incubation with either exogenous PGE2 or selective EP2 agonist significantly increased expression of IL-1RI in NM-C fibroblasts and had hardly any effect on NP-AERD fibroblasts. Alterations in IL-1RI, COX-2, and mPGES-1 expression that were found in NP-AERD fibroblasts were corrected when EP2 receptor expression was normalized by transfection of NP-AERD fibroblasts. CONCLUSION: Altered expression of EP2 in patients with AERD contributes to deficient induction of IL-1RI, reducing the capacity of IL-1β to increase COX-2 and mPGES-1 expression, which results in low PGE2 production. This impairment in the generation of PGE2 subsequently reduces its ability to induce IL-1RI.
Authors: Elina Jerschow; Matthew L Edin; Yuling Chi; Beth Hurst; Waleed M Abuzeid; Nadeem A Akbar; Marc Gibber; Marvin P Fried; Weiguo Han; Teresa Pelletier; Zhen Ren; Taha Keskin; Gigia Roizen; Fred B Lih; Artiom Gruzdev; J Alyce Bradbury; Victor Schuster; Simon Spivack; David Rosenstreich; Darryl C Zeldin Journal: J Allergy Clin Immunol Pract Date: 2018-12-21
Authors: Whitney W Stevens; Anju T Peters; Annemarie G Hirsch; Cara M Nordberg; Brian S Schwartz; Dione G Mercer; Mahboobeh Mahdavinia; Leslie C Grammer; Kathryn E Hulse; Robert C Kern; Pedro Avila; Robert P Schleimer Journal: J Allergy Clin Immunol Pract Date: 2017-03-09
Authors: Whitney W Stevens; Elina Jerschow; Alan P Baptist; Larry Borish; John V Bosso; Kathleen M Buchheit; Katherine N Cahill; Paloma Campo; Seong H Cho; Anjeni Keswani; Joshua M Levy; Anil Nanda; Tanya M Laidlaw; Andrew A White Journal: J Allergy Clin Immunol Date: 2020-12-09 Impact factor: 10.793