# Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies
## 2 Pathogenesis of Cystic Fibrosis (CF)
### Complications Associated with Mutation of CFTR and Hyperactivation of ENaC  
The major complications of CF include lung destruction and respiratory failure [53]. Owing to a mutation in the CFTR encoding the chloride channel found in the apical membrane of several epithelial cells, including the lungs, the level of apical Cl- ion reduces, while ENaC activity increases [12; 59; 60; 61]. This leads to an imbalance between the Cl- ion secretion and Na+ ion absorption through CFTR and ENaC, respectively. This imbalance depletes the volume of ASL, which is necessary for the clearance of respiratory mucus [59; 62], thereby leading to the formation of thickened dehydrated mucus which serves as a nidus for bacterial infections [60; 63]. In addition, the normal mechanism of mucus clearance depends on the movement of cilia which are located in the apical surface of the epithelial cells inside the periciliary layer (PCL) and their heads across the mucus layer. In normal conditions, cilia can move easily because of the watery layer of PCL that will lead to the removal of the trapped materials in the mucus layer toward the mouth [64]. In CF patients, cilia movement is inhibited due to the thinning of the PCL and the thickened mucus layer, which cannot repel the inhabitant materials, such as microorganisms [64]. This mucus then acts as a barrier for the delivery of drugs either into the mucus layer itself or across it to the airway epithelial cells [62]. Additionally, attainment of homeostasis of the imbalanced fluid and ions leads to the activation of inflammatory responses, primarily the NLRP3 inflammasome [65]. Thus, the accumulation of the thickened mucus inside the airways and the difficulty in its clearance, as well as the chronic bacterial infection and inflammation could contribute to the destruction of the lung and the respiratory failure in CF patients [62].  
One bacterial strain, _Pseudomonas aeruginosa (P. aeruginosa)_, complicates the treatment strategy in CF patients, owing to its ability to colonize new sites and to form biofilms using the quorum sensing system [66; 67]. Hence, the bacterium protects itself from the host immune system and antibiotics [68; 69]. Even if an antibiotic penetrates the biofilm, owing to its ability to survive in low oxygen environments and use aerobic, as well as, anaerobic metabolic pathways (i.e., aerobe to facultative anaer), it is tolerant to most antibiotics (antibiotic resistance), thus making it difficult to eradicate [69; 70; 71]. Microorganisms like _Staphylococcus aureus (S. aureus)_ and other oropharyngeal bacterial flora have proven to be responsible for CF lung infection, either alone or by co-infection with _P. aeruginosa_, resulting in a polymicrobial lung infection [67]. CFTR mutation leads to the presence of thick, dry, and sticky mucus which promotes infection due to enhanced bacterial adherence and lack of bacterial clearance [68]. Therefore, it is necessary to develop a novel drug delivery system which can penetrate the biofilm and existent mucus to eradicate the bacteria. It is also important to elucidate the mechanism of biofilm formation, and its components, in order to develop a suitable therapeutic strategy.  
Figure 1: Pathogenesis of cystic fibrosis (CF). (**a**) In normal epithelial cells, salt and water secretion is coordinated by cystic fibrosis transmembrane conductance regulator ( CFTR) and absorption via ENaC, which hydrates the airway surface liquid (ASL). (**b**) In CF airway epithelium, defective CFTR impairs Cl– ion and water exchange, causing epithelial sodium channels (ENaC) hyperactivation and leading to dehydrated ASL and thickened mucus, which is considered a conducive environment for infection and inflammation.