Chronic Inflammation in the Cystic Fibrosis Lung: Alterations in Inter- and Intracellular Signaling

A vicious cycle of airway obstruction, infection, and inflammation continues to cause most of the morbidity and mortality in cystic fibrosis (CF). Mutations that result in decreased expression or function of the membrane Cl− channel, cystic fibrosis transmembrane regulator (CFTR), result in a decrease in the volume (and hence the depth) of liquid on the airway surface, impaired ciliary function, and dehydrated glandular secretions. In turn, these abnormalities contribute to a milieu, which promotes chronic infection with a limited but unique spectrum of microorganisms. Defects in CFTR also perturb regulation of several intracellular signaling pathways including signal transducers and activator of transcription, I-κB and nuclear factor-kappa B, and low molecular weight GTPases. Together, these abnormalities result in excessive production of NF-κB dependent cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF), IL-6, and IL-8. There are decreased responses to interferon gamma and transforming growth factor beta leading to decreased production of iNOS and NO. Abnormalities of lipid mediators and decreased secretion of counter/regulatory cytokines have also been reported. Together, these effects combine to create a chronic inflammatory process, which damages and obstructs the airways, and eventually claims the life of the patient.