Interdisciplinary approaches for COPD understanding
Group leader Isabelle Dupin
Lung exposure to various types of particles, such as those present in cigarette smoke, can lead to chronic obstructive pulmonary disease (COPD). COPD is a common and devastating respiratory disease, characterized by a progressive airflow obstruction. The chronic course of COPD is frequently worsened by acute exacerbations, which contribute considerably to the worldwide increased mortality, morbidity, and health-care costs associated with the disease.
The disease is characterized by chronic inflammation and bronchial remodeling, in particular peribronchial fibrosis. The extensive immune cell infiltration and changes in tissue structures allows the persistent contact between resident cells (i.e. fibroblast-like cells, epithelial cells) and stimulated immune cells (i.e. CD8+ T cells, CD4+ T cells, neutrophils). We hypothesize that contact between cells, and between cells and the extracellular matrix, is most likely to be a major cause of chronic destructive or fibrotic manifestations.
Our group aims at putting together approaches from different disciplines to investigate the interaction between cells and their microenvironment, in the context of COPD. Lastly, we have focused on the role of fibrocytes, fibroblast-like cells produced by the bone marrow, in COPD. These cells can circulate in the blood and can be recruited into injured tissues (Dupin et al., 2018). We have shown that the level of circulating fibrocytes in peripheral blood is increased during acute exacerbations of COPD patients and that the CXCR4-CXCL12 axis is important for COPD fibrocyte migration (Dupin et al., 2016). We have recently demonstrated an increase of tissue fibrocytes in COPD lungs, which is associated with a degraded lung function and anatomical modifications (Dupin et al., 2019). Those fibrocytes could also perpetuate chronic inflammation, through interaction and activation of CD8+ T cells (Eyraud et al., 2023).
To build organoids modeling distal airways, alveoli and skeletal muscles, reproducing COPD features
The lack of physiological relevance of current cell-based assays, as well as the limited predictibility of tests performed in animal models, strongly limit our understanding of pathophysiological processes and the evaluation of drug efficacy in pre-clinical studies. Thus, we aim at building:
- A tubular model of bronchi, that resemble the phenotype and functionalities of distal airways of COPD patients,
- A reproducible alveolosphere model to better understand emphysema pathophysiology,
- A vascularized skeletal muscle organoid, able to recapitulate features of COPD sarcopenia.
To decipher cellular interactions and their alterations in COPD
We will combine basic and translational approaches together with a combination of advanced imaging, innovative cellular and animal models to investigate cell-cell interactions, in particular those implicating fibrocytes. We will integrate those findings at a tissue scale level using mathematical modelling to understand the transition from a healthy to a diseased state.
To evaluate the efficacy of innovative curative RNA drugs, that could counteract bronchial remodeling and chronic inflammation in COPD
We hope to obtain solid pre-clinical evidences of RNA drugs, obtained in in vitro models made of patient’s cells, and provide a framework to translate preclinical findings to clinical settings. This project is a collaboration with Jeanne Leblond-Chain (INSERM U1212/UMR CNRS 5320, Bordeaux).
CXCR4 blockade alleviates pulmonary and cardiac outcomes in early COPD.
Dupin, I., P. Henrot, E. Maurat, R. Abohalaka, S. Chaigne, D.E. Hamrani, E. Eyraud, R. Prevel, P. Esteves, M. Campagnac, M. Dubreuil, G. Cardouat, C. Bouchet, O. Ousova, J.-W. Dupuy, T. Trian, M. Thumerel, H. Begueret, P.-O. Girodet, R. Martan, M. Zysman, V. Michel, and P. Berger.
BioRXiv. 2023 DOI:10.1101/2023.03.10.529743.
Short-range interactions between fibrocytes and CD8+ T cells in COPD bronchial inflammatory response.
Eyraud, E., E. Maurat, J-M. Sac-Epée, P. Henrot, M. Zysman, P. Esteves, T. Trian, H. Bégueret, P-O. Girodet, M. Thumerel, R. Hustache-Castaing, R. Marthan, F. Levet, P. Vallois, C. Contin-Bordes, P. Berger, I. Dupin.
BioRXiv. 2023 DOI:10.1101/2022.10.21.513138.
Probabilistic Cellular Automata modeling of intercellular interactions in airways: complex pattern formation in patients with Chronic Obstructive Pulmonary Disease.
Dupin, I., E. Eyraud, E. Maurat, J.-M. Sac-Épée, and P. Vallois.
Journal of Theoretical Biology. 2023. 564:111448. DOI:10.1016/j.jtbi.2023.111448.
Muscarinic receptor M3 activation promotes fibrocytes contraction.
Henrot, P., E. Eyraud, E. Maurat, S. Point, G. Cardouat, J-F. Quignard, P. Esteves, T. Trian, P-O Girodet, R. Marthan, M. C. Zysman, P. Berger, I. Dupin.
Frontiers in Pharmacology. 2022 DOI.org/10.3389/fphar.2022.939780.
Circulating fibrocytes as a new tool to predict lung cancer progression after surgery?
Henrot P, Beaufils F, Thumerel M, Eyraud E, Boudoussier A, Begueret H, Maurat E, Girodet PO, Marthan R, Berger P, Dupin I, Zysman M.
Eur Respir J. 2021 Sep 24:2101221. DOI: 10.1183/13993003.01221-2021.
Unravelling the effects of omalizumab on fibrocytes.
Berger. P. and Dupin. I.
Respirology. 2021 DOI: 10.1111/resp.14115
Determination of reliable lung function parameters in intubated mice.
Bonnardel E, Prevel R, Campagnac M, Dubreuil M, Marthan R, Berger P, Dupin I.
Respir Res 2019, 20:211. DOI: 10.1186/s12931-019-1177-9.
Fibrocyte accumulation in the airway walls of COPD patients.
Dupin I, Thumerel M, Maurat E, Coste F, Eyraud E, Begueret H, Trian T, Montaudon M, Marthan R, Girodet PO, Berger P.
Eur Respir J 2019, 54. DOI:10.1183/13993003.02173-2018
Chemokines in COPD: From Implication to Therapeutic Use.
Henrot P, Prevel R, Berger P, Dupin I.
Int J Mol Sci 2019, 20. DOI: 10.3390/ijms20112785
Fibrocytes in Asthma and COPD: Variations on the Same Theme.
Dupin I, Contin-Bordes C, Berger P.
Am J Respir Cell Mol Biol 2018 58:288-298. DOI:10.1165/rcmb.2017-0301PS
Blood fibrocytes are recruited during acute exacerbations of chronic obstructive pulmonary disease through a CXCR4-dependent pathway.
Dupin I, Allard B, Ozier A, Maurat E, Ousova O, Delbrel E, Trian T, Bui HN, Dromer C, Guisset O, Blanchard E, Hilbert G, Vargas F, Thumerel M, Marthan R, Girodet PO, Berger P.
J Allergy Clin Immunol 2016; 137: 1036-1042 e1037. DOI:10.1016/j.jaci.2015.08.043