Fig. 8

CF airway epithelium and pathogen adaptation. Defective CFTR leads to decreased airway surface liquid (ASL) layer. This facilitates microbial colonization and airway inflammation. Pathogen-associated molecular patterns (PAMPs) activate Toll-like receptor (TLR) signaling to activate Interleukin-8 (IL-8) and therefore to recruit polymorphonuclear neutrophils (PMNs). The increasing PMNs result in oxidative stress within the airways by forming reactive oxygen species (ROS). The increased oxidative stress further activates the mitogen activated protein kinase pathway, activating IL-8 and thus recruiting more PMNs. Mutated CFTR in the epithelial cells is unable to channel the antioxidants Glutathione (GSH) and thiocyanate (SCN⁻) into the airway, limiting their ability to counteract the oxidative stress. TLR expression and signaling is also altered in CF epithelium. Expression of TLR2 and TLR5 at the apical surface is increased, whereas TLR4 expression is limited to endosome (not shown here). NF-κB in CF airway epithelial cells is constitutively activated, resulting in the production of inflammatory cytokines including IL-8 and granulocyte macrophage colony stimulating factor (GM-CSF). This also leads to recruitment of PMNs independent of TLR’s interaction with the adaptor protein MyD88. Bacterial PAMPs further increase NF-κB signaling through activation of TLR-MyD88 signaling. The inhaled bacteria start interacting and aggregating to form biofilms. P. aeruginosa also releases outer membrane vesicles containing CF inhibitory factor (Cif), a protein that further inhibits the recycling of CFTR in the host further contributing to the cycle of hyper-inflammation and bacterial colonization