Elsevier

Journal of Cystic Fibrosis

Volume 19, Issue 6, November 2020, Pages 902-909
Journal of Cystic Fibrosis

Original Article
Airway profile of bioactive lipids predicts early progression of lung disease in cystic fibrosis

https://doi.org/10.1016/j.jcf.2020.01.010Get rights and content
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Highlights

  • Abnormal lipid metabolism correlates with early CF lung disease and inflammation.

  • Bioactive lipids and lung damage correlate with cytokines and growth factors in BALF.

  • Bioactive lipids including lysolipids correlate with future structural lung damage.

  • Lysolipid receptor agonist enhances cytokine shedding by airway epithelial cells.

Abstract

Background

Previously, we showed that abnormal levels of bioactive lipids in bronchoalveolar lavage fluid (BALF) from infants with cystic fibrosis (CF) correlated with early structural lung damage.

Method

To extend these studies, BALF bioactive lipid measurement by mass spectrometry and chest computed tomography (CT, combined with the sensitive PRAGMA-CF scoring method) were performed longitudinally at 2-year intervals in a new cohort of CF children (n = 21, aged 1–5 yrs).

Results

PRAGMA-CF, neutrophil elastase activity, and myeloperoxidase correlated with BALF lysolipids and isoprostanes, markers of oxidative stress, as well as prostaglandin E2 and combined ceramide precursors (Spearman's Rho > 0.5; P < 0.01 for all). Multiple protein agonists of inflammation and tissue remodeling, measured by Olink protein array, correlated positively (r = 0.44–0.79, p < 0.05) with PRAGMA-CF scores and bioactive lipid levels. Notably, levels of lysolipids, prostaglandin E2 and isoprostanes at first BALF predicted the evolution of PRAGMA-CF scores 2 years later. In wild-type differentiated primary bronchial epithelial cells, and in CFTR-inducible iCFBE cells, treatment with a lysolipid receptor agonist (VPC3114) enhanced shedding of pro-inflammatory and pro-fibrotic proteins.

Conclusions

Together, our findings suggest that bioactive lipids in BALF correlate with and possibly predict structural lung disease in CF children, which supports their use as biomarkers of disease progression and treatment efficacy. Furthermore, our data suggest a causative role of airway lysolipids and oxidative stress in the progression of early CF lung disease, unveiling potential therapeutic targets.

Keywords

Lysophosphatidic acid
Lysolipid receptor
EGFR
ADAM17
Amphiregulin
Oxidative stress

Abbreviations

ADAM
a disintegrase and metalloproteinase
ALI
air-liquid interface
BAL
bronchoalveolar lavage
BALF
bronchoalveolar lavage fluid
Bx
bronchiectasis
CF
cystic fibrosis
CFSPID
cystic fibrosis Screen Positive, Inconclusive Diagnosis
CFTR
cystic fibrosis transmembrane conductance regulator
CT
computed tomography
Dis
disease score
EGFR
epidermal growth factor receptor
GSH
glutathione
HBEC
human bronchial epithelial culture
HPLC-MS/MS
high-performance liquid chromatography-mass spectrometry
iCFBE
immortalized Cystic fibrosis bronchial epithelial cells
IL-8
Interleukin 8
LPA
lysophosphatidic acid
LPC
lysophosphatidylcholine
MPO
myeloperoxidase
NE
neutrophil elastase
PC
phosphatidylcholine
PCA
Principal component analysis
PG
prostaglandin

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