Abnormal n-6 fatty acid metabolism in cystic fibrosis contributes to pulmonary symptoms

Abstract

Cystic fibrosis (CF) is a recessively inherited fatal disease that is the subject of extensive research and ongoing development of therapeutics targeting the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). Despite progress, the link between CFTR and clinical symptoms is incomplete. The severe CF phenotypes are associated with a deficiency of linoleic acid, which is the precursor of arachidonic acid. The release of arachidonic acid from membranes via phospholipase A₂ is the rate-limiting step for eicosanoid synthesis and is increased in CF, which contributes to the observed inflammation. A potential deficiency of docosahexaenoic acid may lead to decreased levels of specialized pro-resolving mediators. This pathophysiology may contribute to an early and sterile inflammation, mucus production, and to bacterial colonization, which further increases inflammation and potentiates the clinical symptoms. Advances in lipid technology will assist in elucidating the role of lipid metabolism in CF, and stimulate therapeutic modulations of inflammation.

Keywords: Annexin 1; Arachidonic acid; Docosahexaenoic acid; Eicosanoids; Linoleic acid; Mucus.