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Mechanism of disease


Figure 3: Cellular models of electrolyte transport through normal and CF airway epithelia A: In resting conditions, the major active ion transport is amiloride-sensitive absorption of Na+


whose activation raises cellular cAMP, leading to activation of CFTR to provide Cl- C: In CF, due to the absence of CFTR protein and/or its dysfunction, Cl-


and at the same time Na+ moves paracellularly to maintain electroneutrality of epithelium surface. This requires the accumulation of Cl- of the basolateral Na+/K+/2Cl-


channels (CFTR and Ca2+- activated Cl- and K+ channel CaCC), apical Na+ leave the cell via Cl-


paracellular pathway and partially by CFTR. The apical absorption of salts happens due to electrochemical gradient generated by basolateral Na+ accompanied by water transport throughout the epithelium. Cl- B: Chloride ions exit the cell through the apical Cl-


and K+ channels, respectively.


absorption by ENaC slows upon inhibition by CFTR, within the cell through the action


co-transporter. The main sensor for this regulation is ATP, released on the airway surface. Its actions are mediated by purinergic receptors, secretion and negative ENaC regulation by CFTR.


in an increased absorption of sodium, accompanied by paracellular absorption of Cl-


reduced driving force for water to enter the lumen. The overlying mucus is dehydrated and compresses the cilia, resulting in a defective mucociliary clearance and the trapping of bacteria in the mucus.


Innate immunity and inflammation Mutated CFTR affects the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that starts early in infancy and fails to eradicate pulmonary pathogens. Recent reports from studies in neonatal pigs and ferrets give evidence for a primary failure to eradicate bacteria in the CF lung.10


One of the main hypothesis


is that acidic ASL due to defective CFTR may alter the activity of local antimicrobial peptides and impair bacterial killing. CFTR absence or dysfunction has been found to be associated with constitutive activation of pro-inflammatory signaling pathways, such as enhanced NF-κB signaling, as assessed by increased levels


secretion is strongly limited. Secondly in the absence of CFTR, ENaC activity is upregulated, resulting .


of TNF-α, IL-1β and IL-8.11 These critical


mediators, together with elevated levels of IL-6 and leukotriene B4, lead to the excessive polymorphonuclear neutrophil (PMN) influx in the airways and therefore overproduction of elastase, serine protease and reactive oxygen species (ROS), which are themselves pro-inflammatory stimulants. Dysfunctional CFTR do not channel antioxidants, such as glutathione or thiocyanate, into ASL to neutralise the oxidative stress induced by neutrophil infiltration. Neutrophils necrosis also release DNA, which increases mucus viscosity. Interestingly, the PMN of cystic fibrosis patients have delayed constitutive apoptosis, display defect in phagocytosis and bactericidy, which additionally affects the resolution of inflammation. Moreover, increased cell surface expression of specific Toll-like receptors (TLRs: TLR2, TLR5) in human CF epithelia also might amplify inflammatory responses to bacterial products. Regardless of the mechanisms


initiating airway infection, once the airway is colonised by bacteria, a vicious cycle of infection, inflammation and airway damage begins.


In contrast to the high levels of pro-inflammatory cytokines, anti- inflammatory molecules and neutrophil chemotaxis inhibitors, such as IL-10, PPAR (peroxisome proliferation activator receptor), or Lipoxin A4 were found to be significantly decreased in CF. This defect in inflammation resolution amplifies the vicious pro-inflammatory circle.


Defect in autophagy


The most common CFTR mutation, F508del, results in an aggresome-prone protein that is prematurely degraded. This significant ER stress should activate the autophagic pathway in CF airway epithelia, a key process in promoting cellular clearance of protein aggregates. Instead, the accompanying ROS overproduction increases sequestration in


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by ENaC (Epithelial Na+ Channel), inducing absorption of Cl- /K+-


via the ATPase, and is


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