Cystic fibrosis: a hereditary inflammatory process

Abstract

Cystic fibrosis (CF) lung disease is characterized by an exaggerated, and extended inflammation, with a massive influx of neutrophils and high concentrations of interleukin (IL)-8 in bronchoalveolar lavage fluid (BALF). Furthermore, patients with CF have chronic bacterial airway infection, particularly with Pseudomonas aeruginosa. Chronic inflammation and infection lead to structural lung damage and impairment of lung function, finally resulting in respiratory insufficiency. Inflammation starts early in the disease process, even without detectable infection. This in combination with the finding of CFTR mRNA transcripts in blood neutrophils has led to the hypothesis that CF neutrophils are intrinsically altered and that inflammation in CF might be intrinsic. Calcium plays a critical role in several neutrophil functions and regulation of neutrophil migration to the site of infection. We show that fMLP-induced intracellular calcium (Ca2+i) mobilization responses of peripheral blood neutrophils of clinically stable CF patients are increased compared to healthy control neutrophils and these responses cannot be mimicked when healthy control neutrophils were primed with the systemic immune activator TNF-α. Neutrophils differentiated ex-vivo from cord blood CD34+ progenitor cells of a CF and a healthy newborn also displayed an enhanced fMLP-induced Ca2+i response, suggesting an intrinsic neutrophil defect in CF. Furthermore migration of CF neutrophils compared to healthy control neutrophils was enhanced and this migration was abrogated when Ca2+ was depleted from the cells. These results suggest a possible link between the altered Ca2+i mobilization responses and the massive influx of CF neutrophils into the lungs. Studies evaluating inflammation in peripheral blood have shown that inflammation can also be monitored systemically in CF patients with moderate disease. We show that even in young uninfected patients with mild disease priming of peripheral blood neutrophils using expression of newly developed priming associated cellular markers (MoPhabs A17 and A27) is significantly increased. We furthermore show that not only neutrophil priming state is increased, but young CF children with normal lung function and mild disease also display a pro-inflammatory plasma cytokine profile. Structural lung damage in CF can be assessed by chest radiographs. We describe a good correlation between CF chest radiograph scoring systems, pulmonary function tests (PFTs), and other clinical parameters of disease in adolescents with mild to moderate disease. Furthermore we show longitudinal worsening of chest radiograph scores in very young children with CF, while lung function determined by interrupter resistance (Rint) remained normal for most children after 3-years of follow-up. It seems reasonable to intervene in the inflammatory process by starting anti-inflammatory therapy at a young age. We assessed the effects of hydrofluoroalkane beclomethasone dipropionate (HFA-BDP, Qvar) on lung function, inflammation in peripheral blood, chest radiograph scores, bacterial colonization, ETCO, and quality of life in 57 young children with CF. Children treated for 3 years with HFA-BDP show less progression of lung function decline (mean difference between HFA-BDP and placebo treated children 7.5% less decline over 3 years). HFA-BDP treated children also display lower plasma concentrations of pro-inflammatory cytokines, chemokines and soluble adhesion molecules than placebo treated children.