Pro-resolving lipid mediator Resolvin D1 serves as a marker of lung disease in cystic fibrosis

Abstract

BackgroundCystic fibrosis (CF) is an autosomal recessive genetic disorder that affects multiple organs, including the lungs, pancreas, liver and intestine. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) locus lead to defective proteins and reduced Cl- secretion and Na+ hyperabsorption in the affected organs. In addition, patients suffering from CF display chronic inflammation that contributes to the pathogenesis of CF. Recent work suggests that CF patients have a reduced capacity to biosynthesize specialized pro-resolving lipid mediators (SPMs), which contributes to the development and duration of the unwanted inflammation. Alterations in the metabolism of arachidonic acid (AA) and docosahexaenoic acid (DHA) to specialized pro-resolving mediators (SPMs), like lipoxins (LXs), maresins (MaRs), protectins (PDs) and resolvins (Rvs), may play a major role on clinical impact of airway inflammation in CF.MethodsIn this study, our aims were to detect and quantitate Resolvin D1 (RvD1) in sputum and plasma from patients with CF and compare levels of RvD1 with biomarkers of inflammation and lung function. We studied 27 CF patients aged 6 to 55 years (median 16 years) in a prospective approach.ResultsDHA can be found in the plasma of our CF patients in the milligram range and is decreased in comparison to a healthy control group. The DHA-derived pro-resolving mediator Resolvin D1 (RvD1) was also present in the plasma (286.4 ± 50 pg/ mL, mean ± SEM) and sputum (30.0 ± 2.6 pg/ mL, mean ± SEM) samples from our patients with CF and showed a positive correlation with sputum inflammatory markers. The plasma concentrations of RvD1 were ten times higher than sputum concentrations. Interestingly, sputum RvD1/ IL-8 levels showed a positive correlation with FEV1 (rs = 0.3962, p< 0.05).ConclusionsSPMs, like RvD1, are well known to down-regulate inflammatory pathways. Our study shows that the bioactive lipid mediator RvD1, derived from DHA, was present in sputum and plasma of CF patients and may serve as a representative peripheral biomarker of the lung resolution program for CF patients.

Inflammation in cystic fibrosis: An update

“…RvD1 was present in both the plasma and sputum of people with CF. 16 In this study, there was positive correlation between plasma and sputum RvD1 concentrations, but plasma concentrations were 10-fold greater than sputum concentrations in people with CF. These results suggest that RvD1 exerts its effects distally as well as locally.…”

“…The concentration of RvD1 reflects the underlying lung disease severity and eventually may serve as a useful biomarker. RvD1 was present in both the plasma and sputum of people with CF . In this study, there was positive correlation between plasma and sputum RvD1 concentrations, but plasma concentrations were 10‐fold greater than sputum concentrations in people with CF.…”

“…Although RvD1 was present in CF sputum, its increase was not proportional to increases in sputum IL‐8. The ratio of RvD1/IL‐8 positively correlated with FEV 1 , indicating that an imbalance between RvD1 and the pro‐inflammatory mediator it down‐regulates may associate with progressive lung deterioration . Ringholz et al evaluated the impact of RvD1 on airway surface liquid (ASL) height and innate defense in CF .…”

“…The ratio of RvD1/IL-8 positively correlated with FEV 1 , indicating that an imbalance between RvD1 and the proinflammatory mediator it down-regulates may associate with progressive lung deterioration. 16 Ringholz et al evaluated the impact of RvD1 on airway surface liquid (ASL) height and innate defense in CF. 17 Application of RvD1 to primary CF bronchial epithelial cells and to CF cell lines increased ASL height in a dose-dependent fashion, likely through the inhibition of the epithelial sodium channel (ENaC) and other ion transport pathways, rather than through a direct effect on cystic fibrosis transmembrane conductance regulator (CFTR).…”

Sex‐mediated elevation of the specialized pro‐resolving lipid mediator levels in a Sjögren's syndrome mouse model

“…Specifically, RvD1 and LXA 4 levels are reduced in cerebrospinal fluid and hippocampus of Alzheimer's disease patients 51 and RvD3 plasma levels are decreased in a murine model of arthritis 52 . Moreover, a reduced capacity to biosynthesize lipoxins, maresins, protectins, and resolvins was observed in cystic fibrosis patients 53 . Finally, RvD1 levels are decreased in plasma samples derived from patients suffering from systemic lupus erythematosus 54 .…”