Anoctamin 1 dysregulation alters bronchial epithelial repair in cystic fibrosis

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Ruffin, Manon^1,2  Voland, Melanie^1,2  Marie, Solenne^1,2  Bonora, Monique^1,2  Blanchard, Elise^1,2  Blouquit-Laye, Sabine^3,4  Naline, Emmanuel^3,4  Puyo, Philippe⁵  Le Rouzic, Philippe^1,2  Guillot, Loic^1,2  Corvol, Harriet^1,2,6  Clement, Annick^1,2,6  Tabary, Olivier^1,2 

[1] INSERM, U938, F-75012 Paris, France

[2] Univ Paris 06, F-75005 Paris, France

[3] UPRES EA220, Lab Pharmacol, F-92150 Suresnes, France

[4] Univ Versailles St Quentin Yvelines, UFR Sci Sante, Montigny Le Bretonneux, France

[5] Hop Foch, Serv Chirurg Thorac & Transplantat Pulm, Suresnes, France

[6] Hop Trousseau, APHP, Pediat Pulm Dept, F-75571 Paris, France

关键词: Anoctamin 1;    TMEM16a;    Cystic fibrosis;    Airway;    Cell proliferation;    Bronchial epithelial repair;   

DOI  :  10.1016/j.bbadis.2013.09.012

来源: Elsevier

【 摘 要 】

Cystic fibrosis (CF) airway epithelium is constantly subjected to injury events due to chronic infection and inflammation. Moreover, abnormalities in CF airway epithelium repair have been described and contribute to the lung function decline seen in CF patients. In the last past years, it has been proposed that anoctamin 1 (AN01), a Ca2+-activated Cl- channel, might offset the CFTR deficiency but this protein has not been characterized in CF airways. Interestingly, recent evidence indicates a role for ANO1 in cell proliferation and tumor growth. Our aims were to study non-CF and CF bronchial epithelial repair and to determine whether ANO1 is involved in airway epithelial repair. Here, we showed, with human bronchial epithelial cell lines and primary cells, that both cell proliferation and migration during epithelial repair are delayed in CF compared to non-CF cells. We then demonstrated that ANO1 Cl- channel activity was significantly decreased in CF versus non-CF cells. To explain this decreased Cl- channel activity in CF context, we compared ANO1 expression in non-CF vs. CF bronchial epithelial cell lines and primary cells, in lung explants from wild-type vs. F508del mice and non-CF vs. CF patients. In all these models, ANO1 expression was markedly lower in CF compared to non-CF. Finally, we established that ANO1 inhibition or overexpression was associated respectively with decreases and increases in cell proliferation and migration. In summary, our study demonstrates involvement of ANO1 decreased activity and expression in abnormal CF airway epithelial repair and suggests that ANO1 correction may improve this process. (C) 2013 Elsevier B.V. All rights reserved.

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