Patients with cystic fibrosis have serious problems keeping microbe growth in their lungs under control, leading to the morbidity and mortality associated with the disease. In the April issue of Nature Immunology, Christopher Karp and colleagues show that loss of the CFTR chloride ion transporter, encoded by defective CFTR genes, is correlated with reduced lipoxin concentrations in lung secretions. Lack of lipoxin leads to increased lung damage. These findings suggest administration of synthetic lipoxins might prove to be a beneficial therapy for lessening the lung pathology seen in patients with cystic fibrosis.
Lipoxins are tiny lipids that 'switch off' the infection-fighting neutrophils that inadvertently damage the lung when releasing their toxic antimicrobials. Lipoxins convert the immune response from one dominated by neutrophils to one dominated by lymphocytes and macrophages, whose attacks are more focused and produce less collateral damage. With less lipoxin, cystic fibrosis patients experience tremendous tissue damage from their 'overexuberant' neutrophils. This damaged lung environment thus makes them more susceptible to reinfection by bacteria, especially Pseudomonas aeruginosa. This is the reverse of thinking at present, which holds that recurrent infections damage the lung, not the other way around.
The authors then examined a P. aeruginosa infection in a mouse model of compromised lung function. When synthetic lipoxin was administered to these mice, they were able to decrease bacteria numbers faster and had reduced disease severity compared with control mice. These results suggest that the neutrophils are responsible for lung damage, setting up a cycle for recurrent infections and scarring that eventually compromises lung function. These results might also explain the clinical observation that patients with cystic fibrosis do better when they take aspirin or ibuprofen, as these are compounds are related to lipoxin.
Chrisopher L. Karp
University of Cincinnati
Tel: +1 513-636-7608
Additional contact for comment on paper:
University of Tokyo, Japan
Tel: +81 3 5802 2925
Also available online.
(C) Nature Immunology press release.
Message posted by: Trevor M. D'Souza
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