Down-regulation of the Anti-inflammatory Protein Annexin A1 in Cystic Fibrosis Knock-out Mice and Patients

Bensalem, Noura; Ventura, Ana Paula Moraes; Vallée, Béatrice; Lipecka, Joanna; Tondelier, Danielle; Davezac, Noélie; Santos, Alexandre Dos; Perretti, Mauro; Fajac, Anne; Sermet‐Gaudelus, Isabelle; Renouil, M; Lesure, J; Halgand, Frédéric; Laprévôte, Olivier; Edelman, Aleksander

doi:10.1074/mcp.m500019-mcp200

Cited by 86 publications

(74 citation statements)

References 45 publications

(46 reference statements)

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“…Decreased annexin-1 levels have been reported in a mouse model of asthma [52] with a parallel stimulation of cPLA2a activity. The expression of annexin-1 is strongly diminished in nasal cells from CF patients, as well as in lung of Cftr -/-mice [53]. Based on these reports and our findings that cPLA2a activity is increased in lungs of Cftr -/-mice and CF patients, we hypothesise that alteration of levels of one of the components forming this putative complex might impact cPLA2a activity.…”

Section: Cell and Animal Studies F Dif Et Almentioning

confidence: 65%

Critical role of cytosolic phospholipase A2 in bronchial mucus hypersecretion in CFTR-deficient mice

Dif¹,

Yz²,

Burgel³

et al. 2010

European Respiratory Journal

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Cystic fibrosis (CF) is due to mutations in the CF transmembrane conductance regulator gene CFTR. CF is characterised by mucus dehydration, chronic bacterial infection and inflammation, and increased levels of cytosolic phospholipase A2a (cPLA2a) products in airways.We aimed to examine the role of cPLA2a in the modulation of mucus production and inflammation in CFTR-deficient mice and epithelial cells. Mucus production was assessed using histological analyses, immuno-histochemistry and MUC5AC ELISA. cPLA2a activation was measured using an enzymatic assay and lung inflammation determined by histological analyses and polymorphonuclear neutrophil counts in bronchoalveolar lavages.In lungs from Cftr -/-mice, lipopolysaccharide induced mucus overproduction and MUC5AC expression associated with an increased cPLA2a activity. Mucus overproduction was mimicked by instillation of the cPLA2a product arachidonic acid, and abolished by either a cPLA2a null mutation or pharmacological inhibition. An increased cPLA2a activity was observed in bronchial explants from CF patients. CFTR silencing induced cPLA2a activation and MUC5AC expression in bronchial human epithelial cells. This expression was enhanced by arachidonic acid and reduced by cPLA2a inhibition. However, inhibition of CFTR chloride transport function had no effect on MUC5AC expression. Reduction of CFTR expression increased cPLA2a activity. This led to an enhanced mucus production in airway epithelia independent of CFTR chloride transport function. cPLA2a represents a suitable new target for therapeutic intervention in CF.

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Section: Cell and Animal Studies F Dif Et Almentioning

confidence: 65%

Critical role of cytosolic phospholipase A2 in bronchial mucus hypersecretion in CFTR-deficient mice

Dif¹,

Yz²,

Burgel³

et al. 2010

European Respiratory Journal

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“…This would suggest a differential phospholipase activity of the type A1 and/or A2, as this activity would cleave selectively glycerolipid-bound fatty acids if a concomitant variation in lysophospholipids was found, which is not the case. Phospholipase activity and expression in CF tissues has been addressed but not comprehensively ( 11,(38)(39)(40). In general, CF is associated with higher phospholipase A2 activity and expression, but this has been only examined in cell lines ( 39 ) and mouse models ( 11,(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Plasma lipidomics reveals potential prognostic signatures within a cohort of cystic fibrosis patients

Ollero

Astarita

Guerrera

et al. 2011

Journal of Lipid Research

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Cystic fi brosis (CF) is associated with abnormal lipid metabolism. We have recently shown variations in plasma levels of several phosphatidylcholine (PC) and lysophopshatidylcholine (LPC) species related to disease severity in CF patients. Here our goal was to search for blood plasma lipid signatures characteristic of CF patients bearing the same mutation (F508del) and different phenotypes, and to study their correlation with forced expiratory volume in 1 s (FEV1) and Pseudomonas aeruginosa chronic infection, evaluated at the time of testing (t = 0) and three years later (t = 3). Samples from 44 F508del homozygotes were subjected to a lipidomic approach based on LC-ESI-MS. Twelve free fatty acids were positively correlated with FEV1 at t = 0 (n = 29). Four of them (C20:3n-9, C20:5n-3, C22:5n-3, and C22:6n-3) were also positively correlated with FEV1 three years later, along with PC(32:2) and PC(36:4) (n = 31). Oleoylethanolamide (OEA) was negatively correlated with FEV1 progression (n = 17). Chronically infected patients at t = 0 showed lower PC(32:2), PC(38:5), and C18:3n-3 and higher cholesterol, cholesterol esters, and triacylglycerols (TAG). Chronically infected patients at t = 3 showed significantly lower levels of LPC(18:0). These results suggest a potential prognostic value for some lipid signatures in, to our knowledge, the fi rst longitudinal study aimed at identifying lipid biomarkers for CF. -Ollero, M., G. Astarita, I. C. Guerrera, I. Sermet-Gaudelus, S.

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“…Western blot analyses were performed as described elsewhere with slight modifications 15 . Briefly, equal amounts of proteins/lane were electrophoresed on an 8% SDS-PAGE and electrotransferred onto nitrocellulose membranes over 2h at 4°C in Tris-glycine buffer (Biorad) at 200 mA.…”

Section: Cell Culturementioning

confidence: 99%

An unexpected effect of TNF-α on F508del-CFTR maturation and function

et al. 2015

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Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( which encodes a CFTR), cAMP-dependent Cl channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFα is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC) signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFα behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFα has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in

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Down-regulation of the Anti-inflammatory Protein Annexin A1 in Cystic Fibrosis Knock-out Mice and Patients

Cited by 86 publications

References 45 publications

Critical role of cytosolic phospholipase A2 in bronchial mucus hypersecretion in CFTR-deficient mice

Critical role of cytosolic phospholipase A2 in bronchial mucus hypersecretion in CFTR-deficient mice

Plasma lipidomics reveals potential prognostic signatures within a cohort of cystic fibrosis patients

An unexpected effect of TNF-α on F508del-CFTR maturation and function

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