A CECs new discovery compels us to rethink the fundamental mechanisms of mammalian airways’ hydration.

Carlos Flores, CECs Biology Lab researcher, along with Ambra Gianotti, a Doctoral student of Medical Genetics at the University of Genoa (Italy), who completed a residency funded by EMBO (European Molecular Biology Organization), developed a study about electrolyte transport in the trachea using new molecules that inhibit Calcium-activated (TMEM16A) chloride channels. This unexpected discovery revealed that one of these molecules (CaCC-inhA01) also inhibits the CFTR chloride channel. This discovery was later verified and replicated in human cells at the Gianinna Gaslini Molecular Genetics Institute in Genoa, where Ambra developed her Doctoral Thesis work. The result of this work was recently published by the European Journal of Pharmacology.

Mammalian airways create a barrier that protects the organism from possible external aggression. Particularly, this tissue has developed a defense mechanism, which secretes mucus that catches inhaled particles such as, microorganisms (with or without pathogen potential), aside from irritating or toxic molecules derived from human activity (combustion or industrial processes) or those liberated by nature (pollen, etc.), which can affect the functions of the respiratory system or trigger an infection. On second instance the mucus is transported to the oral cavity via the activity of ciliate cells that coat the airways, both processes together account for mucociliary clearance, a key mechanism for healthy lung maintenance.

A key requirement for the airways’ cleansing system to work correctly, is an adequate level of hydration on the airways’ surface, which allows the functioning of mucus layers and its transportation to the oral cavity. A dramatic example of hydration deficiency of the airways is the human condition known as cystic fibrosis, which besides being the most common hereditary disease in humans, it presents severe dehydration of the airways, generating an obstructive condition, recurrent infection with the concomitant destruction of the pulmonary parenchyma and the progressive decay of this organ functions.

In regards to this, Carlos Flores states: “The work developed with Ambra and our collaborators has a direct impact on the knowledge of the mechanisms governing hydration of the airways and underlines the differences that exist in this process between the animal model (mouse) and humans. Furthermore, it describes a never previously reported yet unexpected effect of the activity of the inhibited molecule, which has been widely used in other publications and opens a debate about the interpretation of the results in cellular systems where TMEM16A and CFTR channels coexist.”

Ref.: Gianotti A, Ferrera L, Philp AR, Caci E, Zegarra-Moran O, Galietta LJ & Flores CA. Pharmacological analysis of epithelial chloride secretion mechanisms in adult murine airways. European Journal of Pharmacology. 781:100-8, 2016 http://dx.doi.org/10.1016/j.ejphar.2016.04.007