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1. Glypican-3 is a key tuner of the Hedgehog pathway in COPD

Author

Laure M.G. Petit, Lynda Saber Cherif, Maëva A. Devilliers, Sarah Hatoum, Julien Ancel, Gonzague Delepine, Anne Durlach, Xavier Dubernard, Jean-Claude Mérol, Christophe Ruaux, Myriam Polette, Gaëtan Deslée, Jeanne-Marie Perotin, and Valérian Dormoy

Subjects
COPD, Airway epithelial cells, Hedgehog, GPC3, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis. The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients with chronic obstructive pulmonary disease (COPD). Here, we investigated the co-receptors to fully decipher the complex machinery of airway HH pathway activation in health and COPD. The core elements and co-receptors of HH signalling were investigated in lung cell populations using single-cell RNAseq analysis. The transcript levels of the principal co-receptor GPC3 were investigated on public RNAseq datasets and by RT-qPCR. The localisation of GPC3 was evaluated through immunofluorescent stainings on isolated bronchial AEC and tissues from non-COPD and COPD patients. GPC3 pharmacological modulation was achieved with Codrituzumab during AEC differentiation. We demonstrated that the core elements were not abundant in pulmonary cell populations. Focusing on co-receptors, GPC3 was the most expressed transcript in tracheobronchial epithelial cells. The decrease in GPC3 transcript levels correlated with the severity of airway obstrution in COPD patients. Finally, interfering with GPC3 signalling during AEC differentiation induced downregulation of the HH pathway attested by a decrease of Gli2 leading to reduced ciliogenesis and altered mucin production. GPC3 appears as a crucial co-receptor for the HH pathway in the respiratory context. The modulation of GPC3 may represent a novel experimental strategy to tune HH signalling in therapeutic perspectives.

Published
2025
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2. Primary ciliogenesis is a crucial step for multiciliated cell determinism in the respiratory epithelium

Author

Xavier Dubernard, Randa Belgacemi, Gaëtan Deslée, Jean-Claude Mérol, Christophe Ruaux, Valérian Dormoy, Zania Diabasana, Jeanne-Marie Perotin, Antony Hoarau, Myriam Polette, Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), Clinique mutualiste La Sagesse, Hôpital Maison Blanche, and dormoy, valerian

Subjects
0301 basic medicine, Mucociliary clearance, [SDV]Life Sciences [q-bio], Short Communication, Context (language use), Respiratory Mucosa, Biology, 03 medical and health sciences, 0302 clinical medicine, Ciliogenesis, Homeostasis, Humans, Respiratory system, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Epithelial cell differentiation, Cilium, cilia, airway epithelium, Cell Biology, respiratory system, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], cell differentiation, 030104 developmental biology, 030220 oncology & carcinogenesis, Motile cilium, Molecular Medicine, Respiratory epithelium
Abstract

The alteration of the mucociliary clearance is a major hallmark of respiratory diseases related to structural and functional cilia abnormalities such as chronic obstructive pulmonary diseases (COPD), asthma and cystic fibrosis. Primary cilia and motile cilia are the two principal organelles involved in the control of cell fate in the airways. We tested the effect of primary cilia removal in the establishment of a fully differentiated respiratory epithelium. Epithelial barrier integrity was not altered while multiciliated cells were decreased and mucous‐secreting cells were increased. Primary cilia homeostasis is therefore paramount for airway epithelial cell differentiation. Primary cilia‐associated pathophysiologic implications require further investigations in the context of respiratory diseases.

Published
2021
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3. Chr15q25 Genetic Variant rs16969968 Alters Cell Differentiation in Respiratory Epithelia

Author

Zania, Diabasana, Jeanne-Marie, Perotin, Randa, Belgacemi, Julien, Ancel, Pauline, Mulette, Claire, Launois, Gonzague, Delepine, Xavier, Dubernard, Jean-Claude, Mérol, Christophe, Ruaux, Philippe, Gosset, Uwe, Maskos, Myriam, Polette, Gaëtan, Deslée, Valérian, Dormoy, Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), Clinique mutualiste La Sagesse, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This work was supported by Funding from University of Reims Champagne-Ardenne (Université de Reims Champagne-Ardenne, URCA), the French National Institute of Health and Medical Research (Institut National de la Santé et de la Recherche Médicale, Inserm) and a grant from the Research Institute in Public Health (IReSP) in association with the National Institute of Cancer (INCa). It was carried out in the framework of the Federative Research Structure CAP-Santé and benefited from the Project Research and Innovation in Inflammatory Respiratory Diseases (RINNOPARI)., Sorbonne Université (SU)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and dormoy, valerian

Subjects
Lung Diseases, rs16969968, QH301-705.5, Nerve Tissue Proteins, Respiratory Mucosa, Receptors, Nicotinic, Polymorphism, Single Nucleotide, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], mental disorders, Humans, Genetic Predisposition to Disease, remodelling, Biology (General), QD1-999, Cells, Cultured, Chromosomes, Human, Pair 15, Gene Expression Profiling, Communication, Cell Differentiation, Tobacco Use Disorder, differentiation, Chemistry, Gene Expression Regulation, inflammation, Multigene Family, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, airway epithelial cells
Abstract

International audience; The gene cluster region, CHRNA3/CHRNA5/CHRNB4, encoding for nicotinic acetylcholine receptor (nAChR) subunits, contains several genetic variants linked to nicotine addiction and brain disorders. The CHRNA5 single-nucleotide polymorphism (SNP) rs16969968 is strongly associated with nicotine dependence and lung diseases. Using immunostaining studies on tissue sections and air-liquid interface airway epithelial cell cultures, in situ hybridisation, transcriptomic and cytokines detection, we analysed rs16969968 contribution to respiratory airway epithelial remodelling and modulation of inflammation. We provide cellular and molecular analyses which support the genetic association of this polymorphism with impaired ciliogenesis and the altered production of inflammatory mediators. This suggests its role in lung disease development.

Published
2021
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4. Contribution of molecular tools for the diagnosis and epidemiology of fungal chronic rhinosinusitis

Author

Pauline Comacle, François Le gall, Sorya Belaz, Jean-Pierre Gangneux, Franck Jegoux, Florence Robert-Gangneux, Christophe Ruaux, Service de Parasitologie-Mycologie [Rennes], Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'ORL et de chirurgie maxillo-faciale [Rennes] = ENT Head and Neck Surgery [Rennes], CHU Pontchaillou [Rennes], Clinique mutualiste La Sagesse, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent

Subjects
0301 basic medicine, Male, Microbiological Techniques, sequence analysis, Chronic rhinosinusitis, Direct examination, Polymerase Chain Reaction, Aspergillus fumigatus, Hospitals, University, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Epidemiology, 030223 otorhinolaryngology, DNA, Fungal, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Rhinitis, Molecular Epidemiology, biology, Chronic sinusitis, General Medicine, Middle Aged, 3. Good health, Fungal sinusitis, Infectious Diseases, PCR, ITS1/ITS2, Molecular Diagnostic Techniques, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Cladosporium, medicine.medical_specialty, 030106 microbiology, Sensitivity and Specificity, Microbiology, Scedosporium, 03 medical and health sciences, Internal medicine, DNA, Ribosomal Spacer, medicine, otorhinolaryngologic diseases, Humans, Sinusitis, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Retrospective Studies, chronic rhinosinusitis, Sequence Analysis, DNA, biology.organism_classification, medicine.disease, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Mycoses, Chronic Disease, fungi
Abstract

International audience; Chronic rhinosinusitis (CRS) rank second at chronic inflammatory diseases in industrialized countries and are an important public health concern. Diagnosis relies on a set of arguments including clinical signs, imaging, histopathologic and mycological analyses of sinus specimens, collected during nasal endoscopy. The sensitivity of fungal cultures is reported to be poor, even when direct examination is positive, thus the epidemiology of fungal chronic sinusitis is ill-known. This study evaluated the sensitivity of molecular diagnosis in 70 consecutive samples (61 patients with CRS) analysed at the University Hospital of Rennes during a 3-year period. DNA detection was performed using a conventional PCR method targeting the ITS1/ITS2 sequence and the resulting amplification products were sequenced. Fungal CRS was proven in 42 patients (69%), of which only 20 (48%) had a positive culture. 37/42 (88%) patients were diagnosed with a fungus ball, 3 with allergic fungal CRS and 2 with undetermined fungal CRS. PCR was positive in all 42 cases and direct sequencing allowed to identify fungi in all cases but one, and detected multiple infection in 3. Aspergillus fumigatus was present in 69% of patients; Cladosporium cladosporoides in 9.5%, Scedosporium sp., A. nidulans and A. flavus in 7% each. In 2/19 patients with negative direct examination, sequencing analysis revealed the presence of Capnobotryella sp. and C. cladosporoides, in clinical settings compatible with fungal sinusitis. In conclusion, ITS1/ITS2 PCR had a twice better sensitivity than culture, and combined sequencing provides accurate epidemiological data on fungal CRS.

Published
2016
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5. Liste des Auteurs

Author

Bernard Azéma, Géraldine Bescond, Hervé Bischoff, Éric Bizaguet, Arnaud Coez, Gilles Guillarm, Bernard Hugon, Jérôme Jilliot, Stéphane Laurent, Frank Lefèvre, François Le Her, Christian Renard, Xavier Renard, Christophe Ruaux, and Alain Vinet

Published
2008
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6. Inflammatory pseudotumour of the nasal cavity and sinuses

Author

Philippe Noret, Benoit Godey, and Christophe Ruaux

Subjects
Nasal cavity, Adult, Male, medicine.medical_specialty, Pathology, medicine.medical_treatment, Disease, Granuloma, Plasma Cell, Nose Diseases, Paranasal Sinus Diseases, Medicine, Humans, business.industry, General Medicine, medicine.disease, eye diseases, Radiation therapy, Natural history, Paranasal sinuses, medicine.anatomical_structure, Otorhinolaryngology, Granuloma, Inflammatory pseudotumor, Histopathology, Nasal Cavity, business, Follow-Up Studies
Abstract

The term inflammatory pseudotumour encompasses a very diverse group of conditions, with different sites, whose only common feature is the absence of a specific histological diagnosis. The histopathological and aetiopathogenic data have been derived from experience in the thoracic, orbital and abdominal forms, which are much more frequent than disease affecting the nasal cavities and sinuses. However, there is no evidence that these data are applicable to sino-nasal pseudotumour. We present a case of inflammatory pseudotumour of the nasal cavity and a review of the literature (19 cases in 30 years) with respect to the clinical and radiological findings, the natural history and the specific management of disease at these sites. Surgery seems to be the best option for this localization. Corticosteroids and radiotherapy may be of value in cases of residual tumour after the histological confirmation of the diagnosis and the exclusion of neoplasia.

Published
2001

7. COX-2 independent effects of Celecoxib sensitize Lymphoma B cells to TRAIL-mediated apoptosis

Author

Laurence Bresson-Bepoldin, Céline Pangault, Anne-Sophie Gallouet, Sylvie Caulet-Maugendre, Marion Travert, Thierry Guillaudeux, Karin Tarte, Thierry Lamy, Fabien Guilloton, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement Français du Sang Bretagne, EFS, Université de Rennes (UNIV-RENNES), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, This work was supported by research funding from the Association pour le Développement de l'Hémato-Oncologie (ADHO). ASG was supported by a PhD studentship from INSERM, Région Bretagne and Université de Rennes 1. We thank the Centre de Ressources Biologiques (CRB)-Santé of Rennes hospital, Pr. Thierry Fest and Patrick Tas for providing non-malignant and follicular lymph nodes, Christophe Ruaux for providing tonsil samples and the BREHAT network for FL bone marrow samples. We also thank Severine Moullec for technical assistance and J-Philippe Stéphant., Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR), and Université de Rennes (UR)-Hôpital Pontchaillou

Subjects
Cancer Research, Time Factors, [SDV]Life Sciences [q-bio], Follicular lymphoma, Apoptosis, TRAIL, TNF-Related Apoptosis-Inducing Ligand, hemic and lymphatic diseases, Tumor Cells, Cultured, Cells, Cultured, bcl-2-Associated X Protein, Non-Hodgkin lymphoma, Sulfonamides, Reverse Transcriptase Polymerase Chain Reaction, Cell Cycle, Drug Synergism, Cell cycle, Flow Cytometry, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Oncology, PGE2, medicine.drug, Lymphoma, B-Cell, Stromal cell, Blotting, Western, Dinoprostone, Immune system, Cell Line, Tumor, medicine, Humans, Tumor microenvironment, Cyclooxygenase 2 Inhibitors, business.industry, Mesenchymal Stem Cells, COX-2, medicine.disease, microenvironment, Coculture Techniques, Lymphoma, Cyclooxygenase 2, Celecoxib, Immunology, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, Pyrazoles, Bone marrow, business
Abstract

Purpose: Despite therapeutic advances, non–Hodgkin lymphomas (NHL) remain incurable. They form a group of neoplasms strongly dependent on their inflammatory microenvironment, which plays an important supportive role in tumor B-cell survival and in the resistance to antitumor immune response. New therapies must consider both tumor cells and their surrounding microenvironment Experimental Design: Stromal cells, derived from bone marrow or lymph nodes, and B cells from follicular lymphoma patients were cocultured or cultured alone with celecoxib treatment, a nonsteroidal anti-inflammatory drug, and/or TRAIL, a promising cytotoxic molecule for cancer therapy. Results: In this study, we show that follicular lymphoma stromal cells produce large amounts of PGE2. This production is abrogated after celecoxib treatment, targeting the COX-2 isoenzyme involved in PGE2 synthesis. Furthermore, we demonstrate that celecoxib increases apoptosis in NHL B-cell lines and in primary follicular lymphoma B cells cocultured with stromal cells, but independently of the PGE2/COX-2 axis. Finally, celecoxib increases the apoptotic activity of TRAIL. We provide evidence that celecoxib affects proliferation and sensitizes NHL B-cell lines to apoptosis through COX-2–independent effects by slowing down the cell cycle and decreasing the expression of survival proteins, such as Mcl-1. Conclusions: These data suggest new potent strategies for NHL therapy combining drugs targeting both tumor B cells and survival signals provided by the tumor microenvironment. Clin Cancer Res; 20(10); 2663–73. ©2014 AACR.

Published
2014
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8. Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure

Author

Stéphanie Pons, Franck Delavoie, Kamel Maouche, Christelle Coraux, Jean-Marie Tournier, Christine Terryn, Uwe Maskos, Isabelle Cloëz-Tayarani, Kahina Medjber, Jean-Marie Zahm, Philippe Birembaut, Plasticité de l'épithélium respiratoire dans les conditions normales et pathologiques - UMR-S 903 (PERPMP), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Université de Reims Champagne-Ardenne (URCA), Interface biomatériaux/Tissus hôtes, Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie intégrative des Systèmes cholinergiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Hôpital Maison Blanche, This work was supported by grants from Vaincre la Mucoviscidose (to C.C. and F.D.), the Lions Club of Soissons and 1 Euro contre le cancer (to P.B.), and by the Région Champagne-Ardenne (K. Maouche and K. Medjber)., We thank Edith Puchelle, Béatrice Nawrocki-Raby, Myriam Polette, Mathilde Viprey, and Thierry Chinet for their insights, Robert L. Dormer for the gift of the MPCT-1 anti-CFTR antibody and Marc Merten for the gift of MM39 and KM4 cell lines, all of the surgeons and ear, nose, and throat doctors who provided us with human airway tissues (Profs. Christian Debry and Gaétan Deslee and Drs. Salima Bellefqih, Maryline Dauphin, Anne Durlach, Karine Joseph, Talal Nasser, Christophe Ruaux, and Dominique Zachar), and Dr. Denis Lamiable for the nicotine and cotinine measurements in mice., Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Neurobiologie intégrative des Systèmes cholinergiques (NISC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Mouse, alpha7 Nicotinic Acetylcholine Receptor, [SDV]Life Sciences [q-bio], MESH: Membrane Microdomains, Cystic Fibrosis Transmembrane Conductance Regulator, chloride efflux, Receptors, Nicotinic, Cystic fibrosis, MESH: Mice, Knockout, MESH: Nicotine, [SCCO]Cognitive science, Mice, 0302 clinical medicine, MESH: Respiratory Mucosa, Cyclic AMP, MESH: Animals, Mucociliary clearance, MESH: Cyclic AMP, Cells, Cultured, MESH: Cystic Fibrosis Transmembrane Conductance Regulator, Mice, Knockout, 0303 health sciences, Multidisciplinary, respiratory system, Biological Sciences, Cystic fibrosis transmembrane conductance regulator, 3. Good health, medicine.anatomical_structure, Nicotinic agonist, 030220 oncology & carcinogenesis, MESH: Calcium, MESH: Receptors, Nicotinic, MESH: Cells, Cultured, medicine.medical_specialty, Nicotine, Respiratory Mucosa, Biology, MESH: alpha7 Nicotinic Acetylcholine Receptor, 03 medical and health sciences, Membrane Microdomains, Chlorides, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Bungarotoxins, medicine, Animals, Humans, MESH: Chlorides, MESH: Mice, 030304 developmental biology, Transepithelial potential difference, Acetylcholine receptor, MESH: Humans, Ion Transport, [SCCO.NEUR]Cognitive science/Neuroscience, Apical membrane, medicine.disease, Bungarotoxins, Epithelium, respiratory tract diseases, MESH: Ion Transport, Mice, Inbred C57BL, Endocrinology, biology.protein, Respiratory epithelium, Calcium, Ciliated cells, submucosal gland
Abstract

Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in α7 knockout mice is characterized by a higher transepithelial potential difference, an increase of amiloride-sensitive apical Na + absorption, a defective cAMP-dependent Cl − conductance, higher concentrations of Na + , Cl − , K + , and Ca 2+ in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of α7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of α7 nAChR to CFTR occurs through Ca 2+ entry and activation of adenylyl cyclases, protein kinase A, and PKC. α7 nAChR, CFTR, and adenylyl cyclase-1 are physically and functionally associated in a macromolecular complex within lipid rafts at the apical membrane of surface and glandular airway epithelium. This study establishes the potential role of α7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.

Published
2013
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