CHAPTER 7: The Discovery of Novel Inhaled ENaC Blockers for the Treatment of Cystic Fibrosis Lung Disease

On a daily basis we can inhale up to 12,000 liters of air, and with this comes a wealth of particles including environmental pollutants, allergens and microbes that impact on the surface epithelium of the lung. The lungs maintain a sterile environment through the utilization of various systems, including phagocytosis of particles by lung resident macrophages, and also through mucociliary (MCC) and cough clearance (CC). An increasing body of data now highlights the degree of lung mucosal hydration as being central to effective MCC and CC, and the salient roles that a number of ion channels can play in the regulation of hydration. This chapter focuses on one of these ion channels – the epithelial sodium channel (ENaC) – and the hypothesis that blocking ENaC in the lung mucosa will result in an enhancement of mucus clearance, thereby reducing the risk of acquiring respiratory infections. A review of the drug discovery approaches to attenuate airway ENaC function, and the status of key experimental compounds in clinical trials, is also provided.