Inflammation In Cystic Fibrosis Lung Disease Research Articles

Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4ratio in children with cystic fibrosis

Airway disease in cystic fibrosis (CF) is characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophilic inflammation. Lipoxin A4 (LXA4) initiates the active resolution of inflammation and promotes airway surface hydration in CF models. 15-Lipoxygenase (LO) plays a central role in the "class switch" of eicosanoid mediator biosynthesis from leukotrienes to lipoxins, initiating the active resolution of inflammation. We hypothesised that defective eicosanoid mediator class switching contributes to the failure to resolve inflammation in CF lung disease. Using bronchoalveolar lavage (BAL) samples from 46 children with CF and 19 paediatric controls we demonstrate that the ratio of LXA4 to leukotriene B4 (LTB4) is depressed in CF BAL (p<0.01), even in the absence of infection (p<0.001). Furthermore, 15-LO2 transcripts were significantly less abundant in CF BAL samples (p<0.05). In control BAL, there were positive relationships between 15-LO2 transcript abundance and LXA4/LTB4 ratio (p=0.01, r=0.66) and with percentage macrophage composition of the BAL fluid (p<0.001, r=0.82), which were absent in CF. Impoverished 15-LO2 expression and depression of the LXA4/LTB4 ratio are observed in paediatric CF BAL. These observations provide mechanistic insights into the failure to resolve inflammation in the CF lung.

Use of modulators of airways inflammation in patients with CF.

One of the hallmarks of cystic fibrosis (CF) lung disease is the presence of intense, neutrophil-dominated airway inflammation, and many researchers have focused on developing therapies to reduce inflammation in CF lung disease. Systemic corticosteroids can delay progression of lung disease, but at the cost of unacceptable side effects. Inhaled corticosteroids are widely used, but their efficacy has yet to be demonstrated in a controlled fashion. Ibuprofen has also been shown to delay disease progression, but its use has been limited by the need to obtain individual pharmacokinetics and concern about side effects. Other treatments with potential anti-inflammatory effects include pentoxifylline, leukotriene antagonists, docosahexaenoic acid, and azithromycin. Few, if any, large clinical studies of these therapies have been published, but several are presently underway. Because neutrophil elastase appears to be a key mediator of tissue damage in CF lung disease, anti-elastase compounds have also been studied, including alpha-1-protease inhibitor, secretory leukocyte protease inhibitor, and small molecule inhibitors. There have been no large-scale controlled trials of these therapies in CF. More recently, investigators have focused on cytokine modulation, using either interleukin-10 or interferon gamma. Some complementary and alternative medicine therapies may also have anti-inflammatory effects, although their clinical value has yet to be demonstrated in a rigorously-controlled fashion. In summary, numerous anti-inflammatory therapies have been applied to CF lung disease, but more large, well-controlled studies will need to be performed to determine their true clinical usefulness.