# Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies
## 2 Pathogenesis of Cystic Fibrosis (CF)
### Hyperactivation of Epithelial Sodium Channels (ENaC)  
Hydration of the epithelial surfaces of different tissues is crucial for tissue homeostasis and normal physiological functions, which is maintained by airway surface liquid (ASL) in the lungs and regulated by ENaC [34]. In addition to controlling the sodium balance, ENaC aids in the maintenance of blood volume and pressure [35]. Therefore, ENaC dysfunction results in a number of local and systemic diseases like renal salt wasting and CF. The former is caused by the loss of ENaC function [36], whereas the latter is developed due to the improper functioning of ENaC [13; 37]. ENaC is a heterotrim protein channel consisting of \(\alpha\), \(\beta\) and \(\gamma\) subunits, and is located in the apical surface of epithelial cells [38]. The \(\alpha\) and \(\gamma\) subunits have extracellular loops, which upon cleavage, activate the ENaC and enhance Na\({}^{+}\) uptake, while the \(\beta\)-subunit reportedly has a regulatory role [39]. In some tissues, such as the brain, kidneys, and human nasal epithelium, a fourth ENaC subunit (\(\delta\)) is present. This fourth subunit alters the biophysical features of the ENaC channels; tetrameric \(\alpha\beta\gamma\delta\)-ENaC channels generate a two-fold constitutive Na\({}^{+}\) current larger than that generated by the trimeric ENaC channels [35; 40]. ENaC activity is regulated by different intracellular and extracellular factors. At the cellular level, the expression of ENaC subunits is under the control of several factors like TGF\(\beta\), serine/threonine kinase SGK1, proteases, and aldosterone [41]. Following its assembly, ENaC is activated via proteolytic cleavage by channel activating protease 1. Several other cellular cascades, like the ERK pathway, ligase protein Nedd4-2, cAMP, PIP2, and purinergic signaling, are implicated in ENaC regulation [42; 43]. Additionally, external factors affecting the expression and activity of ENaC include ions, proteolytic cleavage, and mechanical stress [44]. In the lung airway, regulation of ENaC function is carried out by the CFTR protein, which controls the absorption of Na\({}^{+}\) ions by inhibiting ENaC function [45]. In addition to its regulatory activity, CFTR has an absorptive capacity and works with or against ENaC [46]. Therefore, _CFTR_ mutation is associated with the depletion of Cl\({}^{-}\) ions and concomitant enhancement in the absorption of Na\({}^{+}\) ions. CFTR-independent activation of ENaC has also been reported. For instance, the release of the elastase enzyme by neutrophils and the cleavage of cathepsin B activates the ENaC subunit [47]. During infection, enzymes like protease and alkaline protease that are released by some bacteria can also activate ENaC and elevate Na\({}^{+}\) ion absorption [48]. Moreover, mutation in the genes encoding \(\alpha\) and \(\beta\) subunits induce CF-like illness in the absence of CFTR mutations [49]. In the lungs, the presence of ASL and the consequent mucociliary clearance is mediated by the regulation of Cl\({}^{-}\) ion secretion by CFTR and Na\({}^{+}\) ion absorption by ENaC [34]. The hyperactivation of ENaC generates an osmotic gradient and finally leads to the dehydration of ASL. The consequent accumulation of hyperviscous mucus and impairment of mucociliary movement represent the hallmarks of CF [12; 50]. In contrast to ENaC hyperactivity, mutations leading to ENaC hypoactivity have been reported to cause pseudohypoaldosteronism. This disease is characterized by elevated airway secretions and extremely rapid mucus removal [49; 51]. Although other channels contribute to the hydration of the airway, a balance between CFTR and ENaC is important for the maintenance of homeostasis in the ASL [52]. However, the effect of CFTR on ENaC activity is debatable [53]. Some studies support the notion that ENaC action is abnormal and relies on the CFTR in CF patients [54; 55; 56], while other studies have reported that ENaC activity is unaltered in both CF and normal individuals [57; 58].