R. N. Criner and M. K. Han, COPD care in the 21st century: a public health priority, Respir Care, vol.63, pp.591-600, 2018.

M. Miravitlles, N. Roche, J. Cardoso, D. Halpin, Z. Aisanov et al., Chronic obstructive pulmonary disease guidelines in Europe: a look into the future, Respir Res, vol.19, p.11, 2018.

D. Singh, A. Agusti, A. Anzueto, P. J. Barnes, J. Bourbeau et al., Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the gold science committee report 2019, Eur Respirat J, 2019.

S. Hangaard, T. Helle, C. Nielsen, and O. K. Hejlesen, Causes of misdiagnosis of chronic obstructive pulmonary disease: a systematic scoping review, Respir Med, vol.129, pp.63-84, 2017.

J. A. Stockley, B. G. Cooper, R. A. Stockley, and E. Sapey, Small airways disease: time for a revisit?, Int J Chron Obstruct Pulmon Dis, vol.12, pp.2343-53, 2017.

N. Roche, Stable COPD treatment: where are we?, COPD, vol.15, pp.123-132, 2018.

M. E. Wechsler, Current and emerging biologic therapies for asthma and COPD, Respir Care, vol.63, pp.699-707, 2018.

C. M. Riley and F. C. Sciurba, Diagnosis and outpatient management of chronic obstructive pulmonary disease: a review, JAMA, vol.321, pp.786-97, 2019.

N. Hirota and J. G. Martin, Mechanisms of airway remodeling, Chest, vol.144, pp.1026-1058, 2013.

A. Higham, A. M. Quinn, J. Cançado, and D. Singh, The pathology of small airways disease in COPD: historical aspects and future directions, Respir Res, vol.20, p.49, 2019.

S. S. Sohal, Epithelial and endothelial cell plasticity in chronic obstructive pulmonary disease (COPD), Respir Investig, vol.55, pp.104-117, 2017.

A. E. Tilley, M. S. Walters, R. Shaykhiev, and R. G. Crystal, Cilia dysfunction in lung disease, Annu Rev Physiol, vol.77, pp.379-406, 2015.

A. Yaghi, A. Zaman, G. Cox, and M. B. Dolovich, Ciliary beating is depressed in nasal cilia from chronic obstructive pulmonary disease subjects, Respir Med, vol.106, pp.1139-1186, 2012.

W. Zuo, J. Yang, Y. Strulovici-barel, J. Salit, M. Rostami et al., Exaggerated BMP4 signalling alters human airway basal progenitor cell differentiation to cigarette smoking-related phenotypes, Eur Respir J, vol.53, pp.2553-2017, 2019.

M. C. Kugler, A. L. Joyner, C. A. Loomis, and J. S. Munger, Sonic hedgehog signaling in the lung from development to disease, Am J Respir Cell Mol Biol, vol.52, pp.1-13, 2015.

A. L. Bolaños, C. M. Milla, J. C. Lira, R. Ramírez, M. Checa et al., Role of sonic Hedgehog in idiopathic pulmonary fibrosis, Am J Physiol Lung Cell Mol Physiol, vol.303, pp.978-90, 2012.

C. Wang, N. De-mochel, S. A. Christenson, M. Cassandras, R. Moon et al., Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype, J Clin Invest, vol.128, pp.4343-58, 2018.

G. B. Carballo, J. R. Honorato, G. De-lopes, T. Spohr, and S. E. De, A highlight on sonic hedgehog pathway, Cell Commun Signal, vol.16, p.11, 2018.

J. H. Kong, C. Siebold, and R. Rohatgi, Biochemical mechanisms of vertebrate hedgehog signaling, Development, vol.146, 2019.

J. L. Regan, D. Schumacher, S. Staudte, A. Steffen, J. Haybaeck et al., Noncanonical hedgehog signaling is a positive regulator of the WNT pathway and is required for the survival of colon cancer stem cells, Cell Rep, vol.21, pp.2813-2841, 2017.

D. Brennan, X. Chen, L. Cheng, M. Mahoney, and N. A. Riobo, Noncanonical Hedgehog signaling, Vitam Horm, vol.88, pp.55-72, 2012.

H. Fernandes-silva, J. Correia-pinto, and R. S. Moura, Canonical sonic hedgehog signaling in early lung development, J Dev Biol, vol.5, 2017.

M. C. Kugler, C. A. Loomis, Z. Zhao, J. C. Cushman, L. Liu et al., Sonic hedgehog signaling regulates myofibroblast function during alveolar septum formation in murine postnatal lung, Am J Respir Cell Mol Biol, vol.57, pp.280-93, 2017.

T. Peng, D. B. Frank, R. S. Kadzik, M. P. Morley, K. S. Rathi et al., Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration, Nature, vol.526, pp.578-82, 2015.

A. Sriperumbudur, M. Breitzig, R. Lockey, and N. Kolliputi, Hedgehog: the key to maintaining adult lung repair and regeneration, J Cell Commun Signal, vol.11, pp.95-101, 2017.

S. G. Pillai, D. Ge, G. Zhu, X. Kong, K. V. Shianna et al., A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci, PLoS Genet, vol.5, p.1000421, 2009.

W. J. Kim and S. D. Lee, Candidate genes for COPD: current evidence and research, Int J Chron Obstruct Pulmon Dis, vol.10, pp.2249-55, 2015.

Y. Li, M. H. Cho, and X. Zhou, What do polymorphisms tell us about the mechanisms of COPD?, Clin Sci, vol.131, pp.2847-63, 2017.

S. Mao, A. S. Shah, T. O. Moninger, L. S. Ostedgaard, L. Lu et al., Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling, Proc Natl Acad Sci, vol.115, pp.1370-1375, 2018.

A. Tam, M. Hughes, K. M. Mcnagny, M. Obeidat, T. L. Hackett et al., Hedgehog signaling in the airway epithelium of patients with chronic obstructive pulmonary disease, Sci Rep, vol.9, p.3353, 2019.

D. Rand, I. A. Blaikley, J. Booton, R. Chaudhuri, N. Gupta et al., British thoracic society guideline for diagnostic flexible bronchoscopy in adults: accredited by nice, Thorax, vol.68, pp.1-44, 2013.

T. Ho, R. P. Cusack, N. Chaudhary, I. Satia, and O. P. Kurmi, Under-and over-diagnosis of COPD: a global perspective, Breathe (Sheff), vol.15, pp.346-2018, 2019.

D. Adam, J. Roux-delrieu, E. Luczka, A. Bonnomet, J. Lesage et al., Cystic fibrosis airway epithelium remodelling: involvement of inflammation, J Pathol, vol.235, pp.408-427, 2015.

D. Jiang, N. Schaefer, and H. W. Chu, Air-liquid interface culture of human and mouse airway epithelial cells, Methods Mol Biol, vol.1809, pp.91-109, 2018.

A. C. Schamberger, C. A. Staab-weijnitz, N. Mise-racek, and O. Eickelberg, Cigarette smoke alters primary human bronchial epithelial cell differentiation at the air-liquid interface, Sci Rep, vol.5, p.8163, 2015.

L. M?-uller, L. E. Brighton, J. L. Carson, W. A. Fischer, and I. Jaspers, Culturing of human nasal epithelial cells at the air liquid interface, J Vis Exp, 2013.

A. A. Pezzulo, T. D. Starner, T. E. Scheetz, G. L. Traver, A. E. Tilley et al., The airliquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia, Am J Physiol Lung Cell Mol Physiol, vol.300, pp.25-31, 2011.

S. Ruiz-garcía, M. Deprez, K. Lebrigand, A. Cavard, A. Paquet et al., Novel dynamics of human mucociliary differentiation revealed by single-cell RNA sequencing of nasal epithelial cultures, Development, 2019.

H. R. Maun, X. Wen, A. Lingel, F. J. De-sauvage, R. A. Lazarus et al., Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site, J Biol Chem, vol.285, pp.26570-80, 2010.

J. Ericson, S. Morton, A. Kawakami, H. Roelink, and T. M. Jessell, Two critical periods of sonic hedgehog signaling required for the specification of motor neuron identity, Cell, vol.87, pp.661-73, 1996.

L. C. Wang, Z. Y. Liu, L. Gambardella, A. Delacour, R. Shapiro et al., Regular articles: conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration, J Invest Dermatol, vol.114, pp.901-909, 2000.

R. B. Pepinsky, P. Rayhorn, E. S. Day, A. Dergay, K. P. Williams et al., Mapping sonic hedgehog-receptor interactions by steric interference, J Biol Chem, vol.275, pp.10995-1001, 2000.

R. B. Pepinsky, C. Zeng, D. Wen, P. Rayhorn, D. P. Baker et al., Identification of a palmitic acid-modified form of human sonic hedgehog, J Biol Chem, vol.273, pp.14037-14082, 1998.

N. Chaudary, M. Pintilie, D. Hedley, R. P. Hill, M. Milosevic et al., Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts, Br J Cancer, vol.116, pp.50-57, 2017.

J. M. Donnelly, A. Chawla, J. Houghton, and Y. Zavros, Sonic hedgehog mediates the proliferation and recruitment of transformed mesenchymal stem cells to the stomach, PLoS One, vol.8, p.75225, 2013.

A. C. Alfaro, B. Roberts, L. Kwong, M. F. Bijlsma, and H. Roelink, Ptch2 mediates the Shh response in Ptch1-/-cells, Development, vol.141, pp.3331-3340, 2014.

C. Xiao, S. A. Ogle, M. A. Schumacher, N. Schilling, R. A. Tokhunts et al., Hedgehog signaling regulates E-cadherin expression for the maintenance of the actin cytoskeleton and tight junctions, Am J Physiol Gastrointest Liver Physiol, vol.299, pp.1252-65, 2010.

J. M. Bailey, B. J. Swanson, T. Hamada, J. P. Eggers, P. K. Singh et al., Sonic hedgehog promotes desmoplasia in pancreatic cancer, Clin Cancer Res, vol.14, pp.5995-6004, 2008.

O. Pascual, E. Traiffort, D. P. Baker, A. Galdes, M. Ruat et al., Sonic hedgehog signalling in neurons of adult ventrolateral nucleus tractus solitarius, Eur J Neurosci, vol.22, pp.389-96, 2005.
URL : https://hal.archives-ouvertes.fr/hal-00018205

J. Perotin, C. Coraux, E. Lagonotte, P. Birembaut, G. Delepine et al., Alteration of primary cilia in COPD, Eur Respir J, vol.52, 2018.
URL : https://hal.archives-ouvertes.fr/hal-02431953

Y. Katoh and M. Katoh, Integrative genomic analyses on GLI1: positive regulation of GLI1 by Hedgehog-GLI, TGFbeta-Smads, and RTK-PI3K-AKT signals, and negative regulation of GLI1 by Notch-CSL-HES/HEY, and GPCR-Gs-PKA signals, Int J Oncol, vol.35, pp.187-92, 2009.

L. Giovannini-chami, A. Paquet, C. Sanfiorenzo, N. Pons, J. Cazareth et al., The "one airway, one disease" concept in light of Th2 inflammation, Eur Respir J, vol.52, 2018.

N. Cigna, F. Moshai, E. Brayer, S. Marchal-somme, J. Stervinou et al., The hedgehog system machinery controls transforming growth factor-b-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis, Am J Pathol, vol.181, pp.2126-2163, 2012.

M. C. Kugler, T. Yie, Y. Cai, J. Z. Berger, C. A. Loomis et al., The Hedgehog target GLI1 is not required for bleomycin-induced lung fibrosis, Exp Lung Res, vol.45, pp.22-31, 2019.

T. K. Rimkus, R. L. Carpenter, S. Qasem, M. Chan, and H. Lo, Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors, Cancers (Basel), vol.8, 2016.

M. Kesimer, A. A. Ford, A. Ceppe, G. Radicioni, R. Cao et al., Airway mucin concentration as a marker of chronic bronchitis, N Engl J Med, vol.377, pp.911-933, 2017.

J. Ma, B. K. Rubin, and J. A. Voynow, Mucins, mucus, and goblet cells, Chest, vol.154, pp.169-76, 2018.

L. S. Ostedgaard, T. O. Moninger, J. D. Mcmenimen, N. M. Sawin, C. P. Parker et al., Gel-forming mucins form distinct morphologic structures in airways, Proc Natl Acad Sci, vol.114, pp.6842-6849, 2017.

F. Wu, Y. Zhang, B. Sun, A. P. Mcmahon, and Y. Wang, Hedgehog signaling: from basic biology to cancer therapy, Cell Chem Biol, vol.24, pp.252-80, 2017.

K. N. Falkenstein and S. A. Vokes, Transcriptional regulation of graded Hedgehog signaling, Semin Cell Dev Biol, vol.33, pp.73-80, 2014.

P. Niewiadomski, S. M. Niedzi-o»ka, T. Markiewicz-º,-u-spie-nski, B. Baran, and K. Chojnowska, Gli proteins: regulation in development and cancer, Cells, vol.8, 2019.

H. B. Schiller, D. T. Montoro, L. M. Simon, E. L. Rawlins, K. B. Meyer et al., The human lung cell atlas: a high-resolution reference map of the human lung in health and disease, Am J Respir Cell Mol Biol, vol.61, pp.31-41, 2019.

P. A. Reyfman, J. M. Walter, N. Joshi, K. R. Anekalla, A. C. Mcquattie-pimentel et al., Single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis, Am J Respir Crit Care Med, vol.199, pp.1517-1553, 2019.

J. Ordovas-montanes, D. F. Dwyer, S. K. Nyquist, K. M. Buchheit, M. Vukovic et al., Allergic inflammatory memory in human respiratory epithelial progenitor cells, Nature, vol.560, pp.649-54, 2018.

E. Peer, S. Tesanovic, and F. Aberger, Next-generation Hedgehog/GLI pathway inhibitors for cancer therapy, Cancers (Basel), vol.11, 2019.

H. Xie, B. D. Paradise, W. W. Ma, and M. E. Fernandez-zapico, Recent advances in the clinical targeting of Hedgehog/GLI signaling in cancer, Cells, vol.8, 2019.

D. Girardi, A. Barrichello, G. Fernandes, and A. Pereira, Targeting the Hedgehog pathway in cancer: current evidence and future perspectives, Cells, vol.8, 2019.

A. Salaritabar, I. Berindan-neagoe, B. Darvish, F. Hadjiakhoondi, A. Manayi et al., Targeting Hedgehog signaling pathway: paving the road for cancer therapy, Pharmacol Res, vol.141, pp.466-80, 2019.

M. Sabol, D. Trnski, V. Musani, P. Ozreti-c, and S. Levanat, Role of GLI transcription factors in pathogenesis and their potential as new therapeutic targets, Int J Mol Sci, vol.19, 2018.

X. M. Bustamante-marin and L. E. Ostrowski, Cilia and mucociliary clearance, Cold Spring Harb Perspect Biol, vol.9, p.28241, 2017.

J. A. Whitsett, Airway epithelial differentiation and mucociliary clearance, Ann Am Thorac Soc, vol.15, pp.143-151, 2018.

S. Magaki, S. A. Hojat, B. Wei, A. So, and W. H. Yong, An introduction to the performance of immunohistochemistry, Methods Mol Biol, vol.1897, pp.289-98, 2019.

A. Gandjeva and R. M. Tuder, Lung histological methods, Methods Mol Biol, vol.1809, pp.315-344, 2018.

D. Huang, Y. Wang, J. Tang, and S. Luo, Molecular mechanisms of suppressor of fused in regulating the hedgehog signalling pathway, Oncol Lett, vol.15, pp.6077-86, 2018.

A. M. Holtz, K. A. Peterson, Y. Nishi, S. Morin, J. Y. Song et al., Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning, Development, vol.140, pp.3423-3457, 2013.

D. Prokopenko, P. Sakornsakolpat, H. L. Fier, D. Qiao, M. M. Parker et al., Whole-Genome sequencing in severe chronic obstructive pulmonary disease, Am J Respir Cell Mol Biol, vol.59, pp.614-636, 2018.

E. S. Wan, Y. Li, T. Lao, W. Qiu, Z. Jiang et al., Metabolomic profiling in a hedgehog interacting protein (Hhip) murine model of chronic obstructive pulmonary disease, Sci Rep, vol.7, p.2504, 2017.

M. Jeong, Y. Leem, H. Kim, K. Kang, H. Cho et al., A Shh coreceptor Cdo is required for efficient cardiomyogenesis of pluripotent stem cells, J Mol Cell Cardiol, vol.93, pp.57-66, 2016.

S. Jin, D. C. Martinelli, X. Zheng, M. Tessier-lavigne, and C. Fan, Gas1 is a receptor for sonic hedgehog to repel enteric axons, Proc Natl Acad Sci, vol.112, pp.73-80, 2015.

L. Izzi, M. Morin, S. Laniel, D. Wilkes, B. C. Mille et al., Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation, Dev Cell, vol.20, pp.788-801, 2011.

D. Alapati and E. E. Morrisey, Gene editing and genetic lung disease. basic research meets therapeutic application, Am J Respir Cell Mol Biol, vol.56, pp.283-90, 2017.

A. Dakhama and H. W. Chu, The use of CRISPR-Cas9 technology to reveal important aspects of human airway biology, Methods Mol Biol, vol.1799, pp.371-80, 2018.

B. H. Rosen, M. Chanson, L. R. Gawenis, J. Liu, A. Sofoluwe et al., Animal and model systems for studying cystic fibrosis, J Cyst Fibros, vol.17, pp.28-34, 2018.

J. J. Brewington, E. T. Filbrandt, F. J. Larosa, J. D. Moncivaiz, A. J. Ostmann et al., Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies, JCI Insight, vol.3, 2018.

R. G. Crystal, Airway basal cells. The "smoking gun" of chronic obstructive pulmonary disease, Am J Respir Crit Care Med, vol.190, pp.1355-62, 2014.