CF Airway Inflammation Disproportionate to Infection
Several lines of evidence have indicated that inflammation in CF airways is excessive and sustained relative to the infectious stimulus. In vitro models of CF respiratory epithelial cells have indeed demonstrated the increased release of inflammatory mediators after exposure to inflammatory stimuli compared to cells expressing a normal CFTR, possibly mediated through dysregulation of the transcription factor NF-kB. Excessive inflammation may also result Health Pharmacy from impaired inflammatory control such that the airway response fails to cease, as evidenced from several cell model systems.
However, this phenotype depends greatly on the model system tested. For instance, the comparison of various CF and corrected cell lines demonstrated that uncorrected CF airway epithelial cell lines inconsistently express higher IL-8 levels. Isolated primary airway epithelial cells from CF patients had greater IL-8 concentrations in culture, compared to cells isolated from non-CF patients, but only after exposure to Pseudomonas aeruginosa. However, there was no difference in IL-8 release by sham and genetically corrected CF epithelial cells that were grown in primary culture at an air-liquid interface, or in primary cultures of human cells from control and CF subjects. These studies indicate that there is considerable variability in airway epithelial cell responses to inflammatory stimuli among different cell models systems, and raise questions about the existence of a consistent hyperinflammatory CF phenotype. Better, more reproducible epithelial model systems are being developed.
CF mice have been shown to have significantly higher concentrations of inflammatory mediators in BAL fluid and greater mortality than normal litter-mates following intrabronchial instillation of Pseudomonas-laden agar beads, despite identical bacterial burden in the lungs. However, similar to the results from in vitro models, not all murine studies have shown this relationship.
Higher concentrations of neutrophils or IL-8 were found in the lungs of CF patients compared with control subjects, regardless of the pathogen recov-ered, supporting the concepts of both excessive inflammatory response and impaired inflammatory control. Reduced concentrations of antiinflammatory factors, such as IL-103 and lipoxin, were measured in BAL fluid from patients with CF.