BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. OBJECTIVE: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. METHODS: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. RESULTS: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. CONCLUSIONS AND CLINICAL RELEVANCE: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.
BACKGROUND:Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. OBJECTIVE: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. METHODS: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. RESULTS: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. CONCLUSIONS AND CLINICAL RELEVANCE: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.
Authors: David C Lin; Rakesh K Chandra; Bruce K Tan; Whitney Zirkle; David B Conley; Leslie C Grammer; Robert C Kern; Robert P Schleimer; Anju T Peters Journal: Am J Rhinol Allergy Date: 2011 Jul-Aug Impact factor: 2.467
Authors: Mahboobeh Mahdavinia; Roderick G Carter; Christopher J Ocampo; Whitney Stevens; Atsushi Kato; Bruce K Tan; Robert C Kern; David B Conley; Rakesh Chandra; Kathryn E Hulse; Lydia A Suh; James E Norton; Anju T Peters; Leslie C Grammer; Lawrence B Schwartz; Robert P Schleimer Journal: J Allergy Clin Immunol Date: 2014-03-15 Impact factor: 10.793
Authors: Aurélien Trompette; Eva S Gollwitzer; Koshika Yadava; Anke K Sichelstiel; Norbert Sprenger; Catherine Ngom-Bru; Carine Blanchard; Tobias Junt; Laurent P Nicod; Nicola L Harris; Benjamin J Marsland Journal: Nat Med Date: 2014-01-05 Impact factor: 53.440
Authors: J A Poposki; S Peterson; K Welch; R P Schleimer; K E Hulse; A T Peters; J Norton; L A Suh; R Carter; K E Harris; L C Grammer; B K Tan; R K Chandra; D B Conley; R C Kern; A Kato Journal: Clin Exp Allergy Date: 2015-02 Impact factor: 5.018
Authors: Eli O Meltzer; Daniel L Hamilos; James A Hadley; Donald C Lanza; Bradley F Marple; Richard A Nicklas; Claus Bachert; James Baraniuk; Fuad M Baroody; Michael S Benninger; Itzhak Brook; Badrul A Chowdhury; Howard M Druce; Stephen Durham; Berrylin Ferguson; Jack M Gwaltney; Michael Kaliner; David W Kennedy; Valerie Lund; Robert Naclerio; Ruby Pawankar; Jay F Piccirillo; Patricia Rohane; Ronald Simon; Raymond G Slavin; Alkis Togias; Ellen R Wald; S James Zinreich Journal: Otolaryngol Head Neck Surg Date: 2004-12 Impact factor: 3.497
Authors: Kendle M Maslowski; Angelica T Vieira; Aylwin Ng; Jan Kranich; Frederic Sierro; Di Yu; Heidi C Schilter; Michael S Rolph; Fabienne Mackay; David Artis; Ramnik J Xavier; Mauro M Teixeira; Charles R Mackay Journal: Nature Date: 2009-10-29 Impact factor: 49.962
Authors: Swan Lin; Jennifer Racz; Melissa F Tai; Kristina M Brooks; Phillip Rzeczycki; Lauren J Heath; Michael W Newstead; Theodore J Standiford; Gus R Rosania; Kathleen A Stringer Journal: Pharm Res Date: 2015-08-01 Impact factor: 4.200
Authors: William Yip; Xuan Li; Graeme J Koelwyn; Stephen Milne; Fernando Sergio Leitao Filho; Chen Xi Yang; Ana I Hernández Cordero; Julia Yang; Cheng Wei Tony Yang; Tawimas Shaipanich; Stephan F van Eeden; Janice M Leung; Stephen Lam; Kelly M McNagny; Don D Sin Journal: Biomedicines Date: 2022-05-11
Authors: A Wallimann; W Magrath; K Thompson; T Moriarty; R G Richards; C A Akdis; L O'Mahony; C J Hernandez Journal: Eur Cell Mater Date: 2021-04-21 Impact factor: 4.325
Authors: Krist Helen Antunes; José Luís Fachi; Rosemeire de Paula; Emanuelle Fraga da Silva; Laís Passariello Pral; Adara Áurea Dos Santos; Greicy Brisa Malaquias Dias; José Eduardo Vargas; Renato Puga; Fabiana Quoos Mayer; Fábio Maito; Carlos R Zárate-Bladés; Nadim J Ajami; Marcella Ramos Sant'Ana; Thamiris Candreva; Hosana Gomes Rodrigues; Marcio Schmiele; Maria Teresa Pedrosa Silva Clerici; José Luiz Proença-Modena; Angélica Thomas Vieira; Charles R Mackay; Daniel Mansur; Mauricio T Caballero; Jacqui Marzec; Jianying Li; Xuting Wang; Douglas Bell; Fernando P Polack; Steven R Kleeberger; Renato T Stein; Marco Aurélio Ramirez Vinolo; Ana Paula Duarte de Souza Journal: Nat Commun Date: 2019-07-22 Impact factor: 14.919