Specialised pro-resolving mediators play a central role in the pathogenesis of cystic fibrosis
Cystic fibrosis is caused by a mutation to the cystic fibrosis transmembrane conductance (CFTR) gene and affects many organs in which the CFTR protein is expressed; however progressive pulmonary destruction is the main cause of morbidity and mortality. In healthy lungs, mucociliary clearance, which requires optimum hydration of the airway liquid surface, expels inhaled particles, microorganisms and allergens towards the pharynx, where they can be expectorated; this provides protection from inflammation and infection. Although this has been known for decades, the pathogenesis of lung disease in cystic fibrosis is not fully understood.
In cystic fibrosis, the inflammatory reaction is characterised by a predominantly neutrophilic component and increased concentrations of proinflammatory mediators. Patients with cystic fibrosis soon develop excessive inflammation of the airways, which persists even in the absence of infection. The main factors that maintain inflammation are an increase in neutrophil recruitment and their deficient elimination. Furthermore, the neutrophils have functional defects and their loss of bactericidal capacity contributes to persisting infection and inflammation. Efferocytosis and deficient mucociliary clearance result in the necrosis of neutrophils in the airways; this causes the release of toxic and proinflammatory compounds and the recruitment of more neutrophils, leading to the persistence of inflammation. The excessive inflammatory response in cystic fibrosis appears to be due to inefficiency in containing infection and the abnormality of the resolution phase.
Studies indicate that abnormal fatty acid metabolism in cystic fibrosis plays a central role in the disease and persistent inflammation of the airways is related to an abnormal eicosanoid class switch between specialised pro-resolving mediators (SPMs), lipoxins and resolvins, and leukotrienes. The role of SPMs in resolving inflammation, increasing the airway surface liquid layer, favouring bacterial clearance and repairing in tissue suggests that alterations to the production of SPMs plays a central role in the pathogenesis of cystic fibrosis.