SCIENCE

Targeting inflammation resolution, a new therapeutic paradigm using the body’s own ability to modulate inflammatory responses, thus resolving inflammation without inducing immunosuppression.

 

AA/DHA imbalance: a target supported by a strong rationale linked to the expression of the basic defect in CFTR

CF patients have long been known to have abnormalities in the levels of polyunsaturated fatty acids in blood and tissues, particularly with increased levels of arachidonic acid (AA) and decreased docosahexaenoic acid (DHA). Alterations in fatty acid levels are a consistent feature in all CF patients and have been validated in both in patients and in multiple animal models of the disease.

This lipid imbalance was demonstrated to be a primary effect in CF and that organs with the greatest lipid imbalance are also the organs most affected by the disease.

Inflammation is a dynamic multimediated process promoting the immune response and tissue healing. AA-mediated metabolic pathway regulates the inflammation onset, followed by DHA- mediated resolution of inflammation, establishing host response homeostasia. CF gene defect causes exaggerated AA-mediated inflammation, and low DHA-mediated resolution, leading to lung infection and local tissue destruction.

Previous research on CFTR-knockout mice, revealed several candidate genes involved in cellular physiological processes as well as in the immune response, which might contribute to the development of lung disease before infection with Pseudomonas aeruginosa. A strong correlation between the severity of CF lung disease and lipid dysregulation was also demonstrated.