Molecular bases of cigarette smoke-induced COPD

Contacts

Group leader, MCF Maylis Dagouassat

Tél.: 01 49 81 37 25
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Research focus:

Chronic obstructive pulmonary disease (COPD), a cigarette smoking related disease, is defined by a slowly progressive and irreversible airflow obstruction due to two anatomic wounds: an emphysema which is described as a destruction of the lung parenchyma, resulting in dyspnea and exercise limitation, and an airways remodeling characterized by a peri-bronchial fibrosis. No curative treatment is currently available for this disease predicted to be in 2030 the third worldwide cause of death. Currently, the molecular mechanisms leading to the development of COPD are not completely elucidated. However, chronic inflammation and oxidative stress are the main hallmarks of this disease.

In recent years, we focused our work on two mechanisms which participate in this inflammation: cell senescence and autophagy. Cell senescence is characterized by an irreversible loss of replicative capacity associated with secretion of inflammatory mediators (cytokines, chemokines, growth factors, lipids mediators, MMPs….) which are referred to as senescence-associated secretome or SASP. This senescence can stem from shortening of telomeres during continuous cell replication (replicative senescence) or be triggered by other stressors, such as oxidative stress or inflammatory mediators (premature senescence). In response to these signals, two main pathways are activated respectively: p53-p21 and p16-retinoblastoma protein (pRb). The autophagy on the other hand, is a protective mechanism which eliminates aging and dysfunctional organelles (mitophagy) and proteins damaged by oxidative stress exposure (macroautophagy). Lately, several studies suggest an impaired autophagy in COPD and therefore this mechanism may have a potential deleterious effect on this disease. Moreover, autophagy is partly regulated by the chloride channel CFTR.

This work is developed along 4 axes:

1)To determine the role of cell senescence in peri-bronchial fibrosis

2)To characterize the SASP of senescent cells and study the effects on neighboring cells and the signaling pathways activated

3)To identify new signaling pathways leading to cell senescence (in particular to evaluate the impact of autophagy)

4)To determine the role of CFTR and its mutations on autophagy

This work shall allow us to better understand the mechanisms leading to the development of COPD and to find biomarkers and therapeutic targets in reliance on cohorts of patients with or without COPD.

Recent results:

Cigarette smoke induces human CCR6⁺ Th17 lymphocytes senescence and VEGF-A secretion (Sci Rep, 2020)

The induction of heme oxygenase (an antioxidant protein) protects against mitochondria dysfunction by restoring mitophagy and attenuating senescence in COPD fibroblasts (Aging cell, 2018)

The expression of Beclin (an autophagy regulator) is decreased in the sera of patients with COPD (Cell Death Dis, 2018)

Wnt 5A released by senescent COPD lung fibroblasts attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation ( Exp. Med, 2017)

Lung fibroblasts share repair properties with mesenchymal stem cells, which are decreased in COPD via the overactivation of hedgehog signaling pathway (Plos one, 2016)

PGE2 (a lipid mediator) induces the senescence of COPD lung fibroblast via a signaling pathway involving EP2/4/COX2/ROS/p53 (AJRCCM, 2013)

These works lead to two European patents

EP12305514: A method to inhibit senescence and inflammation in chronic obstructive pulmonary disease. 2013

EP19306235.3:  method and composition for diagnosing chronic obstructive pulmonary disease. 2019

Selected publications