INSERM UMR 1152

Team 1
Physiopathology of severe asthma and obstructive lung diseases
Coordinator : Dr Marina PRETOLANI (marina.pretolani@inserm.fr)

Research areas

The origin, progression and symptoms of lung disease, including asthma and chronic obstructive pulmonary disease (COPD), result from a chronic immunoinflammatory reaction and airway remodelling. These phenomena are the consequence, in part, of alterations in the functional and physical barrier properties of the epithelium of the respiratory tract following its damage by allergens, pathogens and pollutants, including cigarette smoke. Asthma and COPD are considered to be heterogeneous diseases manifested by distinct clinical phenotypes (e.g. atopic / non-atopic, obese, frequent exacerbators, with fixed bronchial obstruction) and molecular and histopathological endotypes (T2 and / or T17 polarization). This heterogeneity may explain the absence or very limited effects of some treatments, including corticosteroids, in controlling clinical manifestations and airway inflammation in certain patient subpopulations. It is therefore necessary to better characterize these phenotypes and endotypes in order to identify new biomarkers and more efficient and specific therapeutic targets.

The research program carried out by this Team focuses on the following main objectives:

• identify the specific characteristics and biomarkers of airway inflammation and remodelling, as well as new genes, transcripts and abnormally expressed proteins that characterize new phenotypes / endotypes of severe asthma and COPD patients, particularly in relation to their response to treatment;
• study the mechanisms by which the bronchial epithelium initiates (loss of integrity induced by allergens, fibrogenic growth factors, and pathogens, in particular Aspergillus fumigatus) and spreads (excessive activation and abnormal repair), inflammation and airway remodelling in severe asthma and COPD;
• test new interventional approaches (for example, bronchial thermoplasty, and bio-therapies), to limit inflammation and airway remodelling and improve respiratory function in severe asthmatics, partially or not controlled by current therapies.

In parallel, this Team develops another line of research, which focuses on the study of epithelial alterations accompanying Obliterating Bronchiolitis (BO) in lung transplantation. In this context, the mechanisms involved in the interaction between primary human bronchial epithelial cells and immune cells in a stable state, or under chronic rejection and BO are studied.

Cross-cutting approaches are developed to carry out these projects and they include: (i) studies on the national multi-center cohorts, COBRA and COLT, using genetic, transcriptomic (e.g. scRNAseq) and biological approaches, (ii) identification of new factors and biomarkers in the circulation and the bronchial/alveolar compartment which characterize distinct clinical phenotypes, in particular those which respond little or not to current treatments, (iii) the determination of the functional role of these factors in healthy primary respiratory cells and patients with asthma, COPD or who have undergone lung transplantation, and in a model of bronchiolar epithelial injury/repair and lung remodelling induced by naphthalene in mice.

Key words: severe asthma, COPD, bronchial epithelium, airway smooth  muscle, lung repair and remodelling, inflammation, lung transplantation, cohorts, bio-markers

Main recent scientific publications

1. Dagher R, Copenhaver AM, Besnard V, Berlin A, Hamidi F, Maret M, Wang J, Qu X, Shrestha Y, Wu J, Gautier G, Raja R, Aubier M, Kolbeck R, Humbles AA, Pretolani M. IL-33-ST2 axis regulates myeloid cell differentiation and activation enabling effective club cell regeneration. Nat Commun. 2020 Sep 22;11(1):4786.
2. Leite-de-Moraes M, Belo R, Dietrich C, Soussan D, Aubier M, Pretolani M. Allergy. Circulating IL-4, IFNγ and IL-17 conventional and Innate-like T-cell producers in adult asthma. 2020 Jun 30. Online ahead of print.
3. Dupin C, Belhadi D, Guilleminault L, Gamez AS, Berger P, De Blay F, Bonniaud P, Leroyer C, Mahay G, Girodet PO, Raherison C, Fry S, Le Bourdellès G, Proust A, Rosencher L, Garcia G, Bourdin A, Chenivesse C, Didier A, Couffignal C, Taillé C. Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort. Clin Exp Allergy. 2020 Jul;50(7):789-798.
4. Taillé C, Chanez P, Devouassoux G, Didier A, Pison C, Garcia G, Charriot J, Bouée S, Gruber A, Pribil C, Bourdin A, Humbert M. Mepolizumab in a population with severe eosinophilic asthma and corticosteroid dependence: results from a French early access programme. Eur Respir J. 2020 Jun 25;55(6):1902345.
5. Messika J, Eloy P, Roux A, Hirschi S, Nieves A, Le Pavec J, Sénéchal A, Saint Raymond C, Carlier N, Demant X, Le Borgne A, Tissot A, Debray MP, Beaumont L, Renaud-Picard B, Reynaud-Gaubert M, Mornex JF, Falque L, Boussaud V, Jougon J, Mussot S, Mal H; French Group of Lung Transplantation. COVID-19 in Lung Transplant Recipients. Transplantation. 2020 Oct 30. Online ahead of print
6. Mal H, Santin G, Cantrelle C, Durand L, Legeai C, Cheisson G, Saint-Marcel L, Pipien I, Durin L, Bastien O, Dorent R.Effect of Lung-Protective Ventilation in Organ Donors on Lung Procurement and Recipient Survival Am J Respir Crit Care Med. 2020 Jul 15;202(2):250-258.
7. Nordon C, Grimaldi-Bensouda L, Pribil C, Nachbaur G, Amzal B, Thabut G, Marthan R, Aubier M; COBRA Study Group. Clinical and economic burden of severe asthma: A French cohort study. Respir Med. 2018 Nov;144:42-49.
8. Fernandes J, Hamidi F, Leborgne R, Beau R, Castier Y, Mordant P, Boukkerou A, Latgé JP, Pretolani M. Penetration of the Human Pulmonary Epithelium by Aspergillus fumigatus Hyphae. J Infect Dis. 2018 Sep 8;218(8):1306-1313.
9. Brugière O, Roux A, Le Pavec J, Sroussi D, Parquin F, Pradère P, Dupin C, Bunel V, Mourin G, Jebrak G, Dauriat G, Castier Y, Mordant P, Lortat-Jacob B, Jean-Baptiste S, Mal H, Suberbielle C, Gautreau C, Caillat-Zucman S, Cazes A, Thabut G, Taupin JL. Role of C1q-binding anti-HLA antibodies as a predictor of lung allograft outcome. Eur Respir J. 2018 Aug 23;52(2).
10. Hin A, Kannengiesser C, Roussel A, Renaud-Picard B, Roux A, Reynaud-Gaubert M, Claustre J, Tissot A, Guillemain R, Mornex JF, Mussot S, Dromer C, Dahan M, Brugière O, Mercier O, Borie R, Pretolani M, Castier Y, Mordant P; COLT Consortium. Donor Club Cell Secretory Protein G38A Polymorphism Is Associated With a Decreased Risk of Primary Graft Dysfunction in the French Cohort in Lung Transplantation. 2018 Aug;102(8):1382-1390.
11. Dupin C, Lhuillier E, Létuvé S, Pretolani M, Thabut G, Mal H, Carosella E, Schilte C, Mordant P, Castier Y, Bunel V, Danel C, Rouas-Freiss N, Brugière O. Inhibition of T Cell Alloreactivity by Bronchial Epithelium Is Impaired in Lung Transplant Recipients, Through Pathways Involving TGF-β, IL-10 and HLA-G. 2017 Sep;101(9):2192-2199.
12. Pretolani M, Soussan D, Poirier I, Thabut G, Aubier M; COBRA Study Group; COBRA cohort Study Group. Clinical and biological characteristics of the French COBRA cohort of adult subjects with asthma. Eur Respir J. 2017 Aug 24;50(2).
13. Boddaert G, Mordant P, Le Pimpec-Barthes F, Martinod E, Aguir S, Leprince P, Raux M, Couëtil JP, Fiore A, Lescot T, Malgras B, Pons F, Castier Y. Surgical management of penetrating thoracic injuries during the Paris attacks on 13 November 2015. Eur J Cardiothorac Surg. 2017 Jun 1;51(6):1195-1202.
14. Morer L, Choudat L, Dauriat G, Durand F, Cazals-Hatem D, Thabut G, Brugière O, Castier Y, Mal H. Liver Involvement in Patients With PiZZ-Emphysema, Candidates for Lung Transplantation. Am J Transplant. 2017 May;17(5):1389-1395.
15. Debray MP, Dombret MC, Pretolani M, Thabut G, Alavoine L, Brillet PY, Taillé C, Khalil A, Chanez P, Aubier M. Early computed tomography modifications following bronchial thermoplasty in patients with severe asthma. Eur Respir J. 2017 Mar 15;49(3).
16. Pretolani M, Bergqvist A, Thabut G, Dombret MC, Knapp D, Hamidi F, Alavoine L, Taillé C, Chanez P, Erjefält JS, Aubier M. Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: Clinical and histopathologic correlations. J Allergy Clin Immunol. 2017 Apr;139(4):1176-1185.
17. Taillé C, Grootenboer-Mignot S, Estellat C, Roy C, Ly Ka So S, Pretolani M, Aubier M, Crestani B, Chollet-Martin S. Periplakin is a target for autoimmunity in asthma. Respir Res. 2016 Oct 7;17(1):126.
18. Mordant P, Nakajima D, Kalaf R, Iskender I, Maahs L, Behrens P, Coutinho R, Iyer RK, Davies JE, Cypel M, Liu M, Waddell TK, Keshavjee S. Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation. J Heart Lung Transplant. 2016 Oct;35(10):1245-1254.
19. Aubier M, Thabut G, Hamidi F, Guillou N, Brard J, Dombret MC, Borensztajn K, Aitilalne B, Poirier I, Roland-Nicaise P, Taillé C, Pretolani M. Airway smooth muscle enlargement is associated with protease-activated receptor 2/ligand overexpression in patients with difficult-to-control severe asthma. J Allergy Clin Immunol. 2016 Sep;138(3):729-739.e11.
20. Taillé C, Rouvel-Tallec A, Stoica M, Danel C, Dehoux M, Marin-Esteban V, Pretolani M, Aubier M, d'Ortho MP. Obstructive Sleep Apnoea Modulates Airway Inflammation and Remodelling in Severe Asthma. PLoS One. 2016 Mar 2;11(3):e0150042.