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

Horati, Hamed; Janssens, Hettie M.; Margaroli, Camilla; Veltman, Mieke; Stolarczyk, Marta; Kilgore, Matthew B.; Chou, Jeffrey; Peng, Limin; Tiddens, Harm; Chandler, Joshua D.; Tirouvanziam, Rabindra; Scholte, Bob J.

doi:10.1016/j.jcf.2020.01.010

Cited by 16 publications

(12 citation statements)

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“…The data highlight the enhanced inducible cytokine CXCL5 involved in neutrophil recruitment, tissue remodeling and COPD ( Chen et al, 2019 ), and placental growth factor (PGF) which is induced in the lung hyperoxia response, involved in macrophage polarization and angiogenesis, and exacerbates pulmonary fibrosis ( Zhao et al, 2019 ; Zhang et al, 2020 ). Both proteins correlated with oxidative stress markers, inflammation, and lung CT scores in CF infant BALF ( Horati et al, 2020 ), consistent with a role of these epithelial factors in early CF lung disease. Interestingly the T-cell activator CCL17 was reduced in CF HBEC media ( Figure 8 , Table 2 ), which may be related to the low T-cell count in CF infant BAL ( Scholte et al, 2019 ) and abnormal T-cell maturation in advanced CF lung disease ( Hayes et al, 2020 ).…”

Section: Discussionsupporting

confidence: 57%

“…Previous studies of CF children have demonstrated abnormal levels of polyunsaturated fatty acids (PUFA), sphingolipids, and several lipid markers of oxidative stress, and these defects correlate with CF inflammatory lung disease and tissue remodeling in patients ( Scholte et al, 2019 ; Horati et al, 2020 ) and in animal models ( Freedman et al, 1999 ; Guilbault et al, 2009 ; Veltman et al, 2016 ). In particular, these studies revealed higher levels of the oxidative stress markers methionine sulfoxide ( Chandler et al, 2018 ), isoprostanes, and lysolipids ( Scholte et al, 2019 ; Horati et al, 2020 ) in broncho-alveolar lavage fluid (BALF) from human CF infants compared to non-CF infants, despite comparable inflammation and a lack of detectable bacterial infection. Furthermore, we reported an increased ratio of long-chain to very long-chain ceramide species (LCC/VLCC; Scholte et al, 2019 ), confirming results with plasma from CF patients and in lung tissue and plasma from CF transmembrane conductance regulator (CFTR) knockout mice ( Garic et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, we reported an increased ratio of long-chain to very long-chain ceramide species (LCC/VLCC; Scholte et al, 2019 ), confirming results with plasma from CF patients and in lung tissue and plasma from CF transmembrane conductance regulator (CFTR) knockout mice ( Garic et al, 2017 ). Moreover, the increase in LCC/VLCC ratio in BALF from CF infants was positively correlated with chest computed tomography (CT) scores and multiple pro-inflammatory markers ( Scholte et al, 2019 ; Horati et al, 2020 ) and altered recruitment, differentiation, and activity of neutrophils in the BALF of CF infants ( Margaroli et al, 2019 ). Using the Cftr tm1eur F508del CFTR mouse model, in the absence of bacterial infection, we observed abnormal sphingosine phosphate (S1P) metabolism that correlated with enhanced lung macrophage and neutrophil infiltration, abnormal polarization of dendritic cells, increased mucus production, and enhanced responses to Lipo-saccharide (LPS) challenge, which could be partially corrected with a S1P lyase inhibitor ( Veltman et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

et al. 2021

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A deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) function in CF leads to chronic lung disease. CF is associated with abnormalities in fatty acids, ceramides, and cholesterol, their relationship with CF lung pathology is not completely understood. Therefore, we examined the impact of CFTR deficiency on lipid metabolism and pro-inflammatory signaling in airway epithelium using mass spectrometric, protein array. We observed a striking imbalance in fatty acid and ceramide metabolism, associated with chronic oxidative stress under basal conditions in CF mouse lung and well-differentiated bronchial epithelial cell cultures of CFTR knock out pig and CF patients. Cell-autonomous features of all three CF models included high ratios of ω-6- to ω-3-polyunsaturated fatty acids and of long- to very long-chain ceramide species (LCC/VLCC), reduced levels of total ceramides and ceramide precursors. In addition to the retinoic acid analog fenretinide, the anti-oxidants glutathione (GSH) and deferoxamine partially corrected the lipid profile indicating that oxidative stress may promote the lipid abnormalities. CFTR-targeted modulators reduced the lipid imbalance and oxidative stress, confirming the CFTR dependence of lipid ratios. However, despite functional correction of CF cells up to 60% of non-CF in Ussing chamber experiments, a 72-h triple compound treatment (elexacaftor/tezacaftor/ivacaftor surrogate) did not completely normalize lipid imbalance or oxidative stress.Protein array analysis revealed differential expression and shedding of cytokines and growth factors from CF epithelial cells compared to non-CF cells, consistent with sterile inflammation and tissue remodeling under basal conditions, including enhanced secretion of the neutrophil activator CXCL5, and the T-cell activator CCL17. However, treatment with antioxidants or CFTR modulators that mimic the approved combination therapies, ivacaftor/lumacaftor and ivacaftor/tezacaftor/elexacaftor, did not effectively suppress the inflammatory phenotype.We propose that CFTR deficiency causes oxidative stress in CF airway epithelium, affecting multiple bioactive lipid metabolic pathways, which likely play a role in CF lung disease progression. A combination of anti-oxidant, anti-inflammatory and CFTR targeted therapeutics may be required for full correction of the CF phenotype.

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

et al. 2021

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“…This could be an interesting alternative to treat CF inflammatory dysregulation by inhibiting CER synthesis ( Mingione et al., 2020 ). Although there is no consensus regarding the regulation of CER in CF cells currently, even if more recent data have demonstrated their implication on the progression of CF lung disease ( Horati et al., 2020 ; Mingione et al., 2020 ). Consequently, these results have led to the proposal that upregulated inflammation is related to the molecular defect of CF with a strong implication of nuclear factor kappa B (NFκB) or mitogen-activated protein (MAP) kinase pathways with other transcription factors including NFAT, NF-IL6, AP1 and AP2 ( Tabary et al., 1999 ; Tabary et al., 2003 ; Muselet-Charlier et al., 2007 ).…”

Section: Pathophysiology In Cf Airwaysmentioning

confidence: 99%

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

Mitri

Bardin

et al. 2020

Front. Pharmacol.

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Cystic fibrosis (CF) is the most common genetic disorder among Caucasians, estimated to affect more than 70,000 people in the world. Severe and persistent bronchial inflammation and chronic bacterial infection, along with airway mucus obstruction, are hallmarks of CF lung disease and participate in its progression. Anti-inflammatory therapies are, therefore, of particular interest for CF lung disease. Furthermore, a better understanding of the molecular mechanisms involved in airway infection and inflammation in CF has led to the development of new therapeutic approaches that are currently under evaluation by clinical trials. These new strategies dedicated to CF inflammation are designed to treat different dysregulated aspects such as oxidative stress, cytokine secretion, and the targeting of dysregulated pathways. In this review, we summarize the current understanding of the cellular and molecular mechanisms that contribute to abnormal lung inflammation in CF, as well as the new anti-inflammatory strategies proposed to CF patients by exploring novel molecular targets and novel drug approaches.

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“…IL-8 ( Cosgrove et al, 2011 ), proteolytically activating chemokines such as IL-1α or IL-33 ( Clancy et al, 2018 ), and releasing damage associated molecular pattern proteins such as High Mobility Group Box 1 (HMGB1) ( Griffin et al, 2014 ) which binds to the Receptor for Advanced Glycation End-products (RAGE) or facilitates ligand binding to TLR2 and TLR4 ( Lotze and Tracey, 2005 ). NE further contributes to airway inflammation by increasing the expression of pro-inflammatory long chain ceramides ( Karandashova et al, 2018 ; Horati et al, 2020 ); these lipids impact plasma membrane structure and receptor clustering. NE degrades innate immune proteins including lactoferrin and surfactant proteins A and D, and cleaves both complement and complement receptors causing impaired neutrophil and macrophage phagocytic activity ( Voynow et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Glycosaminoglycans as Multifunctional Anti-Elastase and Anti-Inflammatory Drugs in Cystic Fibrosis Lung Disease

2020

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Neutrophil elastase (NE) is a major protease in the airways of patients with cystic fibrosis (CF) that activates airway inflammation by several mechanisms. NE stimulates epithelial toll like receptors (TLR) resulting in cytokine upregulation and release, upregulates MUC5AC, a major airway mucin, degrades both phagocytic receptors and opsonins resulting in both neutrophil and macrophage phagocytic failure, generates oxidative stress via extracellular generation and uptake of heme free iron, and activates other proteases. Altogether, these mechanisms create a significant inflammatory challenge that impairs innate immune function and results in airway remodeling. Currently, a major gap in our therapeutic approach to CF lung disease is the lack of an effective therapeutic strategy targeting active NE and its downstream pro-inflammatory sequelae. Polysulfated glycosaminoglycans (GAGs) are potent anti-elastase drugs that have additional anti-inflammatory properties. Heparin is a prototype of a glycosaminoglycan with both anti-elastase and anti-inflammatory properties. Heparin inhibits NE in an allosteric manner with high potency. Heparin also inhibits cathepsin G, blocks P-selectin and L-selectin, hinders ligand binding to the receptor for advanced glycation endproducts, and impedes histone acetyltransferase activity which dampens cytokine transcription and High Mobility Group Box 1 release. Furthermore, nebulized heparin treatment improves outcomes for patients with chronic obstructive pulmonary disease (COPD), asthma, acute lung injury and smoke inhalation. However, the anticoagulant activity of heparin is a potential contraindication for this therapy to be developed for CF lung disease. Therefore, modified heparins and other GAGs are being developed that retain the anti-elastase and anti-inflammatory qualities of heparin with minimal to no anticoagulant activity. The modified heparin, 2-O, 3-O desulfated heparin (ODSH), maintains anti-elastase and anti-inflammatory activities in vitro and in vivo , and has little residual anticoagulant activity. Heparan sulfate with O-sulfate residues but not N-sulfate residues blocks allergic asthmatic inflammation in a murine model. Polysulfated hyaluronic acid abrogates allergen- triggered rhinosinusitis in a murine model. Finally, nonsaccharide glycosaminoglycan mimetics with specific sulfate modifications can be designed to inhibit NE activity. Altogether, these novel GAGs or GAG mimetics hold significant promise to address the unmet need for inhaled anti-elastase and anti-inflammatory therapy for patients with CF.

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

Cited by 16 publications

References 28 publications

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

Glycosaminoglycans as Multifunctional Anti-Elastase and Anti-Inflammatory Drugs in Cystic Fibrosis Lung Disease

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