sphingosine-1-phosphate and Cystic-Fibrosis

Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets.

Topics: Adaptation, Physiological; Altitude Sickness; Ceramides; Cystic Fibrosis; Hepcidins; Humans; Hypertension, Pulmonary; Hypoxia; Iron; Lysophospholipids; Pulmonary Disease, Chronic Obstructive; Respiratory Distress Syndrome; Sphingolipids; Sphingosine

Osteopenia and increased fracture rates are well-recognized in patients with cystic fibrosis (CF) disease. In CF pathology, F508del is the most common CFTR mutation, with more than 85% of patients carrying it on at least one allele. The underlying molecular defect in CFTR caused by the F508del-CFTR mutation in osteoclastogenesis, i.e., on the generation and bone-resorption activity of osteoclasts (OCs) from peripheral blood-derived monocytes (PBMCs) remained unexplored. We therefore investigated whether the F508del mutation could affect the osteoclastogenic capacity of PBMCs collected from 15 adult patients bearing the F508del-CFTR mutation, to modulate their bone-resorptive abilities and the level of sphingosine-1-phosphate (S1P) produced by OCs, a key factor in the bone mineral density and formation. In the present study, a severe, defective differentiation of CF-F508del PBMCs to CF-F508del OCs without any significant difference in nuclei number per OC was found compared to non-CF healthy PBMCs from 13 subjects after 7-14-days culture periods. We observed a reduced number of formed non-CF healthy OCs in the presence of a selective inhibitor of CFTR chloride conductance (CFTR-Inh

Topics: Adult; Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Lysophospholipids; Middle Aged; Monocytes; Osteoclasts; Osteogenesis; Sequence Deletion; Sphingosine

Recent research has linked sphingolipid (SL) metabolism with cystic fibrosis transmembrane conductance regulator (CFTR) activity, affecting bioactive lipid mediator sphingosine-1-phosphate (S1P). We hypothesize that loss of CFTR function in cystic fibrosis (CF) patients influenced plasma S1P levels. Total and unbound plasma S1P levels were measured in 20 lung-transplanted adult CF patients and 20 healthy controls by mass spectrometry and enzyme-linked immunosorbent assay (ELISA). S1P levels were correlated with CFTR genotype, routine laboratory parameters, lung function and pathogen colonization, and clinical symptoms. Compared to controls, CF patients showed lower unbound plasma S1P, whereas total S1P levels did not differ. A positive correlation of total and unbound S1P levels was found in healthy controls, but not in CF patients. Higher unbound S1P levels were measured in ΔF508-homozygous compared to ΔF508-heterozygous CF patients (

Topics: Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Heterozygote; Homozygote; Humans; Intestinal Diseases; Lung; Lung Transplantation; Lysophospholipids; Male; Middle Aged; Sphingosine

Heart failure (HF) is among the main causes of death worldwide. Alterations of sphingosine-1-phosphate (S1P) signaling have been linked to HF as well as to target organ damage that is often associated with HF. S1P's availability is controlled by the cystic fibrosis transmembrane regulator (CFTR), which acts as a critical bottleneck for intracellular S1P degradation. HF induces CFTR downregulation in cells, tissues and organs, including the lung. Whether CFTR alterations during HF also affect systemic and tissue-specific S1P concentrations has not been investigated. Here, we set out to study the relationship between S1P and CFTR expression in the HF lung. Mice with HF, induced by myocardial infarction, were treated with the CFTR corrector compound C18 starting ten weeks post-myocardial infarction for two consecutive weeks. CFTR expression, S1P concentrations, and immune cell frequencies were determined in vehicle- and C18-treated HF mice and sham controls using Western blotting, flow cytometry, mass spectrometry, and qPCR. HF led to decreased pulmonary CFTR expression, which was accompanied by elevated S1P concentrations and a pro-inflammatory state in the lungs. Systemically, HF associated with higher S1P plasma levels compared to sham-operated controls and presented with higher S1P receptor 1-positive immune cells in the spleen. CFTR correction with C18 attenuated the HF-associated alterations in pulmonary CFTR expression and, hence, led to lower pulmonary S1P levels, which was accompanied by reduced lung inflammation. Collectively, these data suggest an important role for the CFTR-S1P axis in HF-mediated systemic and pulmonary inflammation.

Topics: Animals; Biomarkers; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Disease Susceptibility; Gene Expression; Heart Failure; Lung; Lysophospholipids; Mice; Organ Specificity; Pneumonia; Signal Transduction; Sphingosine; T-Lymphocyte Subsets

Topics: Aldehyde-Lyases; Animals; Biological Transport; Body Weight; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Dendritic Cells; Disease Models, Animal; Enzyme Inhibitors; Epithelial Cells; Imidazoles; Lipopolysaccharides; Lung; Lysophospholipids; Mice, Inbred C57BL; Mucin 5AC; Mutation; Myeloid Cells; N-Formylmethionine Leucyl-Phenylalanine; Oximes; Pneumonia; Salivary Glands; Sphingosine; X-Ray Microtomography