Targeting Inflammation in Cystic Fibrosis

Abstract

disease, such as n –3 polyunsaturated fatty acids, receptor antagonists of the cysteinyl leukotrienes, macrolides, N acetylcysteine, and -1 antitrypsin have shown clinical efficacy or potential for clinical use, but to date no ideal anti-inflammatory agent for CF lung disease has been found [10] . Because of the notable side effects of broad-spectrum anti-inflammatory drugs, a more targeted approach to control inflammation in CF lung disease is needed [4] . The ideal anti-inflammatory drug should efficiently combat deleterious inflammatory components without adverse effects such as impairment of innate immunity. In order to find such treatment, a thorough understanding of the mechanisms of inflammation in the CF lung as well as of the mechanisms of action of anti-inflammatory drugs is warranted. Unfortunately, our knowledge on the mechanisms of inflammation in the CF lung is limited. One of the most striking characteristics of airway inflammation in CF is the predominance, continuous influx, and sustained accumulation of neutrophils with impaired bacterial-killing capacity upon changes due to unopposed proteolytic activity or host-derived stress signals upon entering CF airways [11, 12] . Neutrophils are recruited to the lungs by chemokines and cytokines, amongst which IL-8 is of key importance [13] . IL-8 is produced by airway epithelial cells endogenously or in response to pathogens via activation of the transcriptional regulatory complex NFB signalling, suggesting a central role of this pathway in the pathophysiology of inflammation in CF lung disease [14] . Cystic fibrosis (CF) lung disease starts early in life and is characterized by chronic infection and inflammation. Long-term evidence shows that inflammation is a hallmark of and key contributor to the pathophysiology of CF lung disease, and is associated with the progressive destructive changes that are responsible for most of the morbidity and mortality in CF [1] . Despite the identification of the gene mutation that causes CF, the exact relationship between the basic gene defect and the pathophysiology of the disease still remains unclear. In particular understanding the inflammatory response of the host and the association between infection and inflammation is subject of ongoing debate and research [2, 3] . This is especially important as anti-infectious therapy is the mainstay of CF treatment and anti-inflammatory therapy could represent a major therapeutic target [4] . Several anti-inflammatory agents including corticosteroids and ibuprofen have been investigated for treatment of CF lung disease. Pioneer trials with long-term alternate-day use of oral prednisone in CF patients reported a decrease in lung disease progression and morbidity with maintenance of lung function [5] . However, side effects of systemic corticosteroids have limited their use as a standard therapy, prompting trials with inhaled corticosteroids, which showed no significant benefits [6] . High-dose ibuprofen has been shown to reduce the amount of neutrophils in the lung [7] and slow the decline in lung function and disease progression [8] . However, due to unfavourable side effects, its clinical use is subject to debate [9] . Other anti-inflammatory agents for CF lung Published online: December 2, 2009