title: Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes induced by cigarette smoke.
abstract: Cigarette smoke (CS) induces inflammatory responses characterized by increase of immune cells and cytokine release. Remodeling processes, such as mucus hypersecretion and extracellular matrix protein production, are also directly or indirectly induced by CS. Recently, we showed that activation of the exchange protein directly activated by cAMP (Epac) attenuates CS extract-induced interleukin (IL)-8 release from cultured airway smooth muscle cells. Using an acute, short-term model of CS exposure, we now studied the role of Epac1, Epac2, and the Epac effector phospholipase-Cε (PLCε) in airway inflammation and remodeling in vivo. Compared to wild-type mice exposed to CS, the number of total inflammatory cells, macrophages, and neutrophils and total IL-6 release was lower in Epac2(-/-) mice, which was also the case for neutrophils and IL-6 in PLCε(-/-) mice. Taken together, Epac2, acting partly via PLCε, but not Epac1, enhances CS-induced airway inflammation in vivo. In total lung homogenates of Epac1(-/-) mice, MUC5AC and matrix remodeling parameters (transforming growth factor-β1, collagen I, and fibronectin) were increased at baseline. Our findings suggest that Epac1 primarily is capable of inhibiting remodeling processes, whereas Epac2 primarily increases inflammatory processes in vivo.
authors.affiliation: Department of Molecular Pharmacology and Groningen Research Institute for Asthma and COPD and a.oldenburger@rug.nl.
authors.forename: Anouk
authors.initials: A
authors.lastname: Oldenburger
authors.affiliation: Groningen Research Institute for Asthma and COPD and Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: Department of Molecular Pharmacology and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Bos
authors.affiliation: Department of Molecular Pharmacology and.
authors.forename: Marieke
authors.initials: M
authors.lastname: Smit
authors.affiliation: Department of Pharmacology and Physiology, School of Medicine, University of Rochester, Rochester, NY, USA;
authors.forename: Alan V
authors.initials: AV
authors.lastname: Smrcka
authors.affiliation: Institut National de la Recherche Scientifique (INSERM), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France; Université de Toulouse III, Paul Sabatier, Toulouse, France; and.
authors.forename: Anne-Coline
authors.initials: AC
authors.lastname: Laurent
authors.affiliation: Groningen Research Institute for Asthma and COPD and Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
authors.forename: Junjun
authors.initials: J
authors.lastname: Cao
authors.affiliation: Groningen Research Institute for Asthma and COPD and Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
authors.forename: Machteld
authors.initials: M
authors.lastname: Hylkema
authors.affiliation: Department of Molecular Pharmacology and Groningen Research Institute for Asthma and COPD and.
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
authors.affiliation: Department of Pharmaceutical Sciences, Lloyd L. Gregory School of Pharmacy, Palm Beach Atlantic University, West Palm Beach, Florida, USA.
authors.forename: Harm
authors.initials: H
authors.lastname: Maarsingh
authors.affiliation: Institut National de la Recherche Scientifique (INSERM), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France; Université de Toulouse III, Paul Sabatier, Toulouse, France; and.
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
authors.affiliation: Department of Molecular Pharmacology and Groningen Research Institute for Asthma and COPD and.
authors.forename: Martina
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D056151:Airway Remodeling / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012906:Smoke / Q000009:adverse effects*
chemical_list: D016207:Cytokines; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C486707:Rapgef4 protein, mouse; D012906:Smoke; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: cAMP; exchange protein; phospholipase Cε
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