title: In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis.
abstract: Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of "transient receptor potential vanilloid-4" (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A2, MAPKs, and NF-κB in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti-inflammatory treatments for diseases such as CF.
authors: Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France;
authors: Clémence O
authors: CO
authors: Henry
authors: Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France;
authors: Emilie
authors: E
authors: Dalloneau
authors: Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France;
authors: Maria-Teresa
authors: MT
authors: Pérez-Berezo
authors: Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain;
authors: Cristina
authors: C
authors: Plata
authors: Unité de Défense Innée et Inflammation, Inserm U874, Institut Pasteur, Paris, France;
authors: Yongzheng
authors: Y
authors: Wu
authors: Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France; Service de Réanimation Polyvalente, Centre Hospitalier Régional Universitaire de Tours, Tours, France;
authors: Antoine
authors: A
authors: Guillon
authors: Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France;
authors: Eric
authors: E
authors: Morello
authors: Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France;
authors: Rose-France
authors: RF
authors: Aimar
authors: Université François Rabelais, Tours, France; Inserm UMR1069, Nutrition, Croissance et Cancer, Tours, France; Ion Channels and Cancer network-Canceropole Grand Ouest, Tours, France;
authors: Marie
authors: M
authors: Potier-Cartereau
authors: Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France;
authors: Frédéric
authors: F
authors: Esnard
authors: Inserm UMR-S 903, SFR CAP-SANTE (FED 4231), Université de Champagne-Ardenne, Reims, France;
authors: Christelle
authors: C
authors: Coraux
authors: Cardiovascular Research Center Hamburg and German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and Department of Anaesthesiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Christian
authors: C
authors: Börnchen
authors: Cardiovascular Research Center Hamburg and German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and Department of Anaesthesiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Rainer
authors: R
authors: Kiefmann
authors: Université François Rabelais, Tours, France; Inserm UMR1069, Nutrition, Croissance et Cancer, Tours, France; Ion Channels and Cancer network-Canceropole Grand Ouest, Tours, France;
authors: Christophe
authors: C
authors: Vandier
authors: Unité de Défense Innée et Inflammation, Inserm U874, Institut Pasteur, Paris, France;
authors: Lhousseine
authors: L
authors: Touqui
authors: Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain;
authors: Miguel A
authors: MA
authors: Valverde
authors: Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, Toulouse, France; CNRS U5282, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France;
authors: Nicolas
authors: N
authors: Cenac
authors: Inserm U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; Université François Rabelais, Tours, France; si-tahar@univ-tours.fr.
authors: Mustapha
authors: M
authors: Si-Tahar
mesh_terms: D000072283:A549 Cells; D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling; D003550:Cystic Fibrosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000502:physiology*
chemical_list: C505032:CFTR protein, human; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: calcium channel; chemokines; eicosanoids; lung inflammation; signal transduction