The role of inflammation in the pathophysiology of CF lung disease

Cystic fibrosis (CF) lung disease is characterized by a self-perpetuating cycle of airway obstruction, chronic bacterial infection, and vigorous inflammation that results in structural damage to the airway. CF patients have a predilection for infection with a limited spectrum of distinctive bacteria that initiate a vigorous inflammatory response which is more harmful than protective. The airway epithelial cell, which normally expresses the cystic fibrosis transmembrane conductance regulator (CFTR), directs the inflammatory response. Defects in CFTR are associated with increased production of pro-inflammatory mediators including IL-8, a potent neutrophil chemoattractant that stimulates the influx of massive numbers of neutrophils into the airways. These neutrophils are the primary effector cells responsible for the pathological manifestations of CF lung disease. Documented deficiencies in immunoregulatory molecules such as IL-10 likely contribute to the generation of the excessive and persistent inflammatory response. Since inflammation is a key contributor to the pathogenesis of CF lung disease, anti-inflammatory therapy must assume a larger role in CF until a cure is discovered. To date, attention has focused primarily on the therapeutic potential of systemic and inhaled corticosteroids and the non-steroidal anti-inflammatory drug (NSAID) ibuprofen. Development of new anti-inflammatory therapies that impact intracellular signaling pathways and cell-cell communication molecules likely will have the greatest impact on limiting the excessive production of the inflammatory mediators in the CF lung, thereby slowing the decline in lung function and improving survival.