Hypersecretion in severe airway diseases: an integrated biophysical approach of the Mucociliary aspect of the bronchial epithelium. – mucocil

Chronic airway diseases (severe asthma, COPD) concern hundred million of people. Current treatments do not interfere with the natural history of the diseases and do not stop fast decline of lung function which is a hallmark of severity. Morphological and functional abnormalities of the bronchial epithelium are associated with mucus hyper secretion in the respiratory tract. Bronchial epithelium is a potential target for treatments. In the present proposal, we aim to study mucociliary component of epithelium in severe bronchial diseases contributing to the hypersecretion phenotype using a multidisciplinary approach combining medicine, biology and physics. We will better understand role and abnormalities of bronchial epithelium using an ex vivo fully reconstituted epithelium (air liquid interface cultures) derived from endobronchial biopsies obtained in human with a well-characterized disease phenotype. We will investigate mucociliary component in health and diseased epithelium and its response to various deleterious agents.
Our objectives are:
1-To establish the dynamics of the reconstituted epithelium and its mucocilliary component in vitro and its response to an allergen (HDM: house dust mites), a bacterial product (LPS) and pollutants (CSE /nanoparticles). We aim at investigating the morphology, the proliferation, the differentiation and certain signaling pathways according to the original disease that we will correlate to clinical phenotypic and histopathological data.
2-To show and understand the impairment of the mucocilliary transport with or without deleterious agents by a quantitative physical approach. We aim at quantitatively determining in-situ the rheological properties of mucus by micro-rheology (particle tracking) and the ciliary activity (dyskinesia, beat frequencies and synchronization). We aim at understanding the coupling between the physical and mechanical properties of mucus, the coordinated ciliary activity and the mucus transport. This will allow determining whether disease-related signatures of impaired mucociliary function exist or not. It may help to identify in-depth what is a perfect intervention in the field, and to which extent existing interventions are qualitatively and quantitatively addressing this signature. We aim at understanding the relationship between inflammatory mediators and physical properties of the mucociliary system as well as the role of specific signaling pathways.
3- To investigate the role and potential of mediators derived from the epithelium to activate dendritic cells. These cells represent key players of innate immunity and are partners to respond to epithelium damage. When epithelium mucociliary system is dysfunctioning, one may anticipate activation of innate immunity due to the abnormal persistency of deleterious agents within the microenvironment. We will build collagen structures mimicking sub epithelial level including basement membrane. Using various mediators gradient, we will investigate dendritic cell activation and its pharmacological modulation.
The ambition of the project is to better understand the “hypersecretion phenotype” in severe bronchial diseases. Crucial mediators and contributors of abnormal mucus and ciliated motion, and by consequence innate immunity and dendritic cells involvement, will be identified and targeted.
An ultimate goal is to identify new relevant and surrogate biomarkers to be used in clinical management and new therapeutic avenues to be tested in near future as innovative drugs.