Fig. 2

Development and evolution of a pathological microenvironment in CF airways. From birth to adulthood, CF patients undergo stepwise changes to their airway microenvironment. In the first phase (left), neutrophil start to accumulate in the lumen in response to cues from the underlying epithelium, prior to the advent of chronic infection. The second phase (middle) features the stable coexistence of an even more substantial population of luminal neutrophils with planktonic bacteria (in red, drawn with flagellum to exemplify P. aeruginosa, the gram-negative pathogen most commonly found in CF patients). In the third phase (right), bacteria switch to a resistant and generally avirulent and auxotrophic mode of existence, encased in an extracellular molecular scaffold (mucoid or biofilm forms, in yellow), with a very large population of neutrophils organized as a cast around them. Shown under the epithelium are the critical environmental conditions that change during the formation of this pathological microenvironment, including the degree of airway obstruction (increasing), and luminal levels of oxygen (decreasing as neutrophil activate their reactive oxygen species burst) and lactic acid (increasing with neutrophil glycolytic activity), pH (decreasing as lactic acid accumulates), as well the burden of free NE and DNA (both correlated positively with neutrophil presence)