Ceramide in Cystic Fibrosis: A Potential New Target for Therapeutic Intervention

Wojewodka, Gabriella; Sanctis, Juan Bautista De; Radzioch, Danuta

doi:10.1155/2011/674968

Cited by 21 publications

(16 citation statements)

References 101 publications

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“…The role of sphingolipids in CF lung disease is incompletely understood. Most of the focus has centered on CF-related changes in membrane-bound ceramides (48). Our study points to a role for sphingolipid mediators.…”

Section: Discussionmentioning

confidence: 72%

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Krause

Limberis

et al. 2013

Am J Respir Cell Mol Biol

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Dysfunction of the cystic fibrosis transmembrane regulator (CFTR) leads to chronic inflammation and infection of the respiratory tract. The role of CFTR for cells of the pulmonary immune system is only partly understood. The present study analyzes the phenotype and immune stimulatory capacity of lung dendritic cells (DCs) from CFTR knockout (CF) mice. Total numbers of conventional DCs, plasmacytoid DCs, and CD103-positive DCs were lower in CF mice compared with wild-type (WT) control mice, as was the expression of major histocompatibility complex class II molecules (MHCII), CD40, and CD86. After pulmonary infection with respiratory syncytial virus, DC numbers increased in WT mice but not in CF mice, and the T cellstimulatory capacity of CF DCs was impaired. The culture of CF lung DCs with bronchoalveolar lavage fluid (BALF) from WT mice increased the expression of MHCII, CD40, and CD86. The supplementation of CF BALF with sphingosine-1-phosphate (S1P), a mediator of immune cell migration and activation that is decreased in CF BALF, rescued the reduced expression of MHCII and CD40 in WT lung DCs and human blood DCs. These findings suggest that DCs are impaired in the CF lung, and that altered S1P affects lung DC function. These findings provide a novel link between defective CFTR and pulmonary innate immune dysfunction in CF.

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Section: Discussionmentioning

confidence: 72%

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Krause

Limberis

et al. 2013

Am J Respir Cell Mol Biol

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“…Other investigators have reported a deficiency of ceramide in CF cells and associated this deficiency with an intense lung inflammatory response [31]. Clinical trials of fenretinide to increase CF cell ceramide levels and decrease lung disease in CF patients are currently being developed [31][32][33]. The objectives of these studies are clearly opposite.…”

Section: Lipid Abnormalitiesmentioning

confidence: 99%

Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy

Cantin

Hartl

Konstan

et al. 2015

Journal of Cystic Fibrosis

401

322

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Lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Although CF lung disease is primarily an infectious disorder, the associated inflammation is both intense and ineffective at clearing pathogens. Persistent high-intensity inflammation leads to permanent structural damage of the CF airways and impaired lung function that eventually results in respiratory failure and death. Several defective inflammatory responses have been linked to cystic fibrosis transmembrane conductance regulator (CFTR) deficiency including innate and acquired immunity dysregulation, cell membrane lipid abnormalities, various transcription factor signaling defects, as well as altered kinase and toll-like receptor responses. The inflammation of the CF lung is dominated by neutrophils that release oxidants and proteases, particularly elastase. Neutrophil elastase in the CF airway secretions precedes the appearance of bronchiectasis, and correlates with lung function deterioration and respiratory exacerbations. Anti-inflammatory therapies are therefore of particular interest for CF lung disease but must be carefully studied to avoid suppressing critical elements of the inflammatory response and thus worsening infection. This review examines the role of inflammation in the pathogenesis of CF lung disease, summarizes the results of past clinical trials and explores promising new anti-inflammatory options.

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“…Annexin 1 is a potent PLA 2 and Cox 2 inhibitor [64]. Although the study results in CF concerning ceramides, important for phagocytosis [65], are not unequivocal, the associations to the plasma fatty acid pattern as well as to the CFTR mutations are interesting [66,67], especially since CF patients are known to display defective pseudomonas internalization [68]. The importance of these pathways in CF have further been demonstrated by Radzioch et al showing a normalization of LCPUFA and ceramide levels in CF mice by giving fenrenitide, a IL-1 β inhibiting retinoid, which interferes with the ceramide transformations [66,69].…”

Section: Etiology Of Fatty Acid Disturbancesmentioning

confidence: 99%