The NFκB Signaling in Cystic Fibrosis Lung Disease: Pathophysiology and Therapeutic Potential

Lung disease is the major cause of morbidity and mortality of cystic fibrosis (CF), an autosomal recessive disease caused by mutations in CF transmembrane-conductance regulator (CFTR) gene. In CF, elevated levels of interleukin-8 (IL-8) signaling mediated by the nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappa B) result in chronic infection, neutrophilic inflammation, and progressive airway destruction. The most frequent mutation in the CFTR gene is the deletion of phenylalanine 508 (Delta F508), which results in its endoplasmic reticulum associated degradation (ERAD) by the ubiquitin-proteasome system. The inability of Delta F508-CFTR to reach cell surface leads to inherently high levels of NF kappa B. Severity of CF lung disease depends on the levels of functional CFTR on cell surface that control its chloride transport and NF kappa B mediated innate immune response functions. NF kappa B mediated chronic inflammation is a prominent feature of CF lung disease and the mechanism(s) by which CFTR regulates these inflammatory signaling pathways is becoming apparent. Recent data suggest that CFTR localization to lipid-rafts is critical for regulating NF kappa B mediated innate immune response and chronic CF lung disease. We anticipate that targeting the pathways, which facilitates CFTR's rescue to the cell surface and lipid-rafts, will not only restore CFTR channel function but also control NF kappa B mediated chronic inflammation, although the level of correction may be a critical factor for therapeutic efficacy. We discuss here the mechanisms of NF kappa B induction in CF, pathogenesis of CF lung disease, and novel therapeutic strategies that may help in reversing the chronic CF lung disease. [Discovery Medicine 9(47):346-356, April 2010]