The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

Abstract

Cystic Fibrosis (CF) is a recessive genetic disease due to mutations of the Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene encoding the CFTR chloride channel. The ion transport abnormalities related to CFTR mutation generate a dehydrated airway surface liquid (ASL) layer, which is responsible for an altered mucociliary clearance, favors infections and persistent inflammation that lead to progressive lung destruction and respiratory failure. The inflammatory response is normally followed by an active resolution phase to return to tissue homeostasis, which involves specialized pro-resolving mediators (SPMs). SPMs promote resolution of inflammation, clearance of microbes, tissue regeneration and reduce pain, but do not evoke unwanted immunosuppression. The airways of CF patients showed a decreased production of SPMs even in the absence of pathogens. SPMs levels in the airway correlated with CF patients’ lung function. The prognosis for CF has greatly improved but there remains a critical need for more effective treatments that prevent excessive inflammation, lung damage, and declining pulmonary function for all CF patients. This review aims to highlight the recent understanding of CF airway inflammation and the possible impact of SPMs on functions that are altered in CF airways.

Impact of 1-Year Supplementation with High-Rich Docosahexaenoic Acid (DHA) on Clinical Variables and Inflammatory Biomarkers in Pediatric Cystic Fibrosis: A Randomized Double-Blind Controlled Trial

“…An important aspect of the study was the assessment of biomarkers of inflammation in sputum and peripheral blood samples. It has been shown that RvD1 levels in CF airways could be a contributing factor to chronic airway inflammation, and 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 [35,36]. SPMs are multipotent regulators of inflammation and resolution, acting on multiple molecular and cell targets to limit inflammation and return to homeostasis, with emerging results encouraging SPMs as candidate drugs for treating infection and chronic inflammation in CF patients [37].…”

The Impact of Air Pollution on the Course of Cystic Fibrosis: A Review

“…An important feature of CF airway pathogenesis is the excessive and inefficient inflammatory process that could be explained by an altered resolution of inflammation ( Roesch et al, 2018 ; Briottet et al, 2020 ). The finding that resolution of inflammation differs between Cftr tm1Hgu and WT mice is consistent with this aspect of the clinical description of the CF airway disease.…”

“…SPM also have a therapeutic potential in reversing or preventing pollution-induced inflammation ( Kilburg-Basnyat et al, 2018 ; Lu et al, 2018 ; Thatcher et al, 2019 ). Finally, in the airway of CF patients, the biosynthesis of LXA4 and Resolvin D1 (RvD1) SPM are reduced ( Karp et al, 2004 ; Ringholz et al, 2014 ; Eickmeier et al, 2017 ; Briottet et al, 2020 ; Isopi et al, 2020 ) and related to the sustained levels of pro-inflammatory cytokines and bacterial infection, the altered airway surface hydration and pulmonary function ( Verrière et al, 2012 ; Eickmeier et al, 2017 ; Codagnone et al, 2018 ; Ringholz et al, 2018 ; Isopi et al, 2020 ). Taken together, these data highlight a possible particular pulmonary susceptibility of CF patients exposed to particulate air pollution; under these conditions, insufficient inflammation resolution could favor the onset of a chronic inflammatory condition and accelerated progression of the CF airway disease.…”

Future therapies for cystic fibrosis

“…The inflammatory process in CF is complicated 43 , characterised by early and sustained neutrophil influx and high levels of elastase which correlate with structural damage on imaging even in early life. There is some evidence that normal resolution mechanisms are impaired 44 , so that inflammation can persist even if an infective insult is cleared 45 . There is certainly evidence that inflammation persists when CFTR function is corrected 46 .…”