Bronchial remodeling in COPD

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.

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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).

Current projects

  • To understand fibrocyte functions in COPD lungs

Fibrocytes may participate to lung inflammation, in virtue of their immune properties, or to peribronchial fibrosis, either directly or indirectly. We will combine basic and translational approaches together with a combination of advanced imaging, innovative cellular and animal models, and mathematical modeling to understand in vivo the recruitment and function(s) of fibrocytes.

 

  • To assess the role of fibrocytes in COPD comorbidities

COPD is associated with frequent comorbidities which may contribute to the clinical manifestations and natural history of the disease. Dysregulation of fibrocyte production, survival and/or recruitment into organs outside the lungs may contribute to the development of comorbidities in patients with COPD. We will focus on two major comorbidities: COPD-related cardiovascular diseases, and skeletal muscle dysfunction.

 

  • To build organoids modeling distal airways and alveoli, 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 3D model that resemble the phenotype and functionalities of distal airways of COPD patients, as well as developing an efficient and reproducible alveolosphere model to enable better understanding of emphysema pathophysiology.

 

Main references

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