Inhibition of Mucus Hypersecretion In COPD Exacerbation – IMHICE

We will proceed to the exposure of different groups of mice to cigarette smoke for 4 months intercalated with episodes of infection with Haemophilus influenzae. A group of these mice will be treated in parallel with the inhibitor ATK. Histological and biochemical analyzes will be performed after euthanasia and sacrifice of mice to assess the effects of ATK on the production of mucus, the intensity of inflammatory and respiratory failure. Studies will be conducted in parallel on epithelial cells in culture to study the mechanisms of action of ATK.

Studies on animal model of COPD in exacerbation phase are in process.

Given the impact of COPD in the exacerbation phase in health and the economic burden associated with this disease, we believe that the results generated by this project will be of interest for pharmaceutical industry involved in the development of therapeutic strategies against COPD. Our work will also also have impact on other diseases characterized by bronchial mucus hyper-secretion such as asthma and cystic fibrosis.

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The incidence of chronic obstructive pulmonary disease (COPD) and its associated exacerbations is rising worldwide resulting in large consumption of healthcare resources and costing billions of euros (3.5 and 55 per year in France and Europe respectively). Cigarette smoking outweighs any other etiologic factor in the development of COPD. But, we know now that the progression and severity of COPD are accentuated as a consequence of the exacerbations mediated in large by opportunistic respiratory infections. Indeed, COPD exacerbations (COPDE) represent a significant contributor to morbidity and mortality rates.
Unfortunately, the mechanisms governing the pathogenesis of COPD exacerbations are poorly understood resulting in scarce and inefficient therapies. This is due, on one hand, to poor understanding of its underlying mechanism(s) and the lack of clinically relevant animal experimental models to reproduce it, on the other hand.
One of the hallmarks of COPDE is the chronic hyperproduction of mucus, which contributes considerably to amplification of inflammation, airspace obstruction, and tissue injury and predisposes the host to uncontrolled infections. It is clearly established that mucus overproduction is a strong predictor of the incidence of respiratory infections and death from COPD especially during the exacerbation phase. We have recently identified a new mechanism involved in the mucus hypersecretion in the hereditary disease, cystic fibrosis (CF). We showed that the host enzyme cytosolic phospholipase A2 a (cPLA2a) induces the expression of mucins (major component of mucus) in CF. cPLA2a belongs to a family of enzymes that hydrolyses membrane phospholipids leading to the generation of lysophospholipids and concomitant release of arachidonic acid (AA). AA is further converted to metabolites that have been involved in mucus over-production and the pathogenesis of various lung infectious and inflammatory diseases. Importantly, we found that cPLA2a inhibitor, Arachidonoyl trifluoro ketone (ATK) reduced considerably the production of mucus in CF.

The purpose of this proof-of-concept project is to:
- investigate the relative contribution of cPLA2a to mucus hypersecretion and lung inflammation and injury in COPDE, a mechanism that has not been explored so far.
- and test the efficacy of ATK against COPDE.

This proposal will involve cell-free sysytem and mouse and human cell culture studies and mouse in vivo studies. Regarding this latter, we set up an original mouse model for COPDE. Compared to the already reported models, we are the first to develop a model that mimics as closely as possible COPDE. Mice were exposed to cigarette smoke for 4 months intercalated with episodic intranasal infections with Haemophilus influenzae (see details in the proposal).

Given COPDE impact on healthcare and the high economic burden associated with this disease, we believe that data generated from this project will be of interest to pharmaceutical companies focusing on COPD. Protection of our data through patents and/or development of bio-industrial partnership will be ensured/facilitated by the research valorization office involved in this project. Above all, we hope that this therapeutic approach will help «curb» the abnormal mucus production in COPDE, which should benefit the ill patient and depreciate the economic burden.