Figure 5.

The paradigm of neutrophil recruitment to the CF airway. The airway epithelium, stimulated by microbial antigens, secretes proinflammatory agents and chemoattractants which recruit neutrophils in an attempt to clear the colonizing microorganisms. (1) Following bacterial challenge, neutrophils transmigrate into the airway lumen, where they encounter dehydrated, mucous-rich ASL (green). Segregated from the neutrophil, the bacteria adapt to their environment, for example by generation of an extracellular polymeric matrix. (2) The neutrophil encounters bacteria in a complex setting, including EPM polysaccharides and attempts to phagocytose the invading microorganism. (3) In a healthy airway, the neutrophil will then undergo phagocytosis-induced cell death (PICD) and be cleared by macrophage; however, in CF, phagocytosis is frustrated by the biofilm and neutrophil undergoes apoptosis followed by necrosis. Alternatively, necrosis may be directly induced by the invading pathogen. (4) PICD and (5) pro-resolving signaling are thereby inhibited, so the airway cannot return to a healthy state. (6) Where the neutrophils have not been cleared, they become necrotic and disintegrate; this releases antimicrobial peptides (AMPs) which (7) propagate further inflammation and (8) reenforce the EPM leading, ultimately, to fibrotic lesions and lung damage.