Schematic model of the pathogenic events hypothesized to lead to chronic P. aeruginosa infection in airways of cystic fibrosis patients

(A) On normal airway epithelia, a thin mucus layer resides atop the PCL, shown as clear. The presence of the low-viscosity PCL facilitates efficient mucociliary clearance (denoted by vector). A normal rate of epithelial O₂ consumption (Q_O2; left) produces no O₂ gradients within this thin ASL (denoted by bar).
(B-F) CF airway epithelia.
(B) Excessive CF volume depletion (denoted by vertical arrows) removes the PCL, mucus becomes adherent to epithelial surfaces, and mucus transport slows/stops (bidirectional vector). The raised O₂ consumption (left) associated with accelerated CF ion transport does not generate gradients in thin films of ASL.
(C) Persistent mucus hypersecretion (denoted as mucus secretory gland/goblet cell units) with time increases the height of luminal mucus massages/plugs. The raised CF epithelial Q_O2 generates steep hypoxic gradients in thickened mucus masses.
(D) P. aeruginosa bacteria deposited on mucus surfaces penetrate actively and/or passively (due to mucus turbulence) into hypoxic zones within the mucus masses.
(E) P. aeruginosa adapts to hypoxic niches within mucus masses with increased alginate formation and the creation of macrocolonies.
(F) Macrocolonies resist secondary defenses, including neutrophils, setting the stage for chronic infection. The presence of increased macrocolony density and, to a lesser extent, neutrophils render the now mucopurulent mass hypoxic.