Cystic Fibrosis (CF) is a life threatening recessive condition caused by mutations in the gene coding for the CF Transmembrane conductance Regulator (CFTR) protein. CFTR is expressed chiefly by exocrine epithelia, and its dysfunction in CF patients leads to abnormal ion balance, hydration, pH, and redox properties of exocrine secretions leading to organ disease. Hallmarks of CF airway disease include bronchiectasis, inflammation by polymorphonuclear neutrophils (PMNs) from blood, obstruction by mucus, and infection by bacteria. Airway disease is the main cause of morbidity in CF, starting after birth and progressing at a different pace depending on patients, leading to lung failure. Thus, there is a need to identify improved treatments.
The CFTR protein is a channel for small anions and a regulator of various other transport mechanisms that is expressed chiefly in exocrine epithelia. In the airways, defective CFTR function hampers the reabsorption of luminal glucose and amino acids by the epithelium, driving microbial growth and auxotrophic adaptation. The CF airway epithelium also secretes high levels of pro-inflammatory mediators, even in the absence of overt infection, leading to the recruitment of blood PMNs. Recruited PMNs produce reactive oxygen species (ROS) and release granule enzymes, e.g., myeloperoxidase (MPO), neutrophil elastase (NE), and matrix metalloprotease-9 (MMP-9) which lead to local production of highly active ROS, tissue proteolysis, high luminal amino acid levels, and changes in epithelial cells and glands. NE itself is a highly active protease and can reprogram epithelial cells and glands. Reflecting on its multiple pathological activities, NE activity in the airway fluid has been identified as a strong predictor of declining CF lung function.
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