Abstract
Our aim was to use quantitative and qualitative analyses to gain further insight into the role of ceramide in cystic fibrosis (CF). Sphingolipid ceramide is a known inflammatory mediator, and its accumulation in inflamed lung has been reported in different types of emphysema, chronic obstructive pulmonary disease and CF. CF is caused by a mutation of the chloride channel and associated with hyperinflammation of the respiratory airways and high susceptibility to ongoing infections. We have previously demonstrated that de novo ceramide synthesis is enhanced in lung inflammation and sustains Pseudomonas aeruginosa pulmonary infection in a CF murine model. We used liquid chromatography and matrix-assisted laser desorption/ionization (MALDI) imaging coupled with mass spectrometry, confocal laser scan microscopy and histology analyses to reveal otherwise undecipherable information. We demonstrated that (i) upregulated ceramide synthesis in the alveoli is strictly related to alveolar infection and inflammation, (ii) alveolar ceramide (C16) can be specifically targeted by nanocarrier delivery of the ceramide synthesis inhibitor myriocin (Myr) and (iii) Myr is able to downmodulate pro-inflammatory lyso-PC, favouring an increase in anti-inflammatory PCs. We concluded that Myr modulates alveolar lipids milieu, reducing hyperinflammation and favouring anti-microbial effective response in CF mouse model.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aguilera-Romero A, Gehin C, Riezman H (2014) Sphingolipid homeostasis in the web of metabolic routes. Biochim Biophys Acta 1841(5):647–656. doi:10.1016/j.bbalip.2013.10.014
Airola MV, Hannun YA (2013) Sphingolipid metabolism and neutral sphingomyelinases. Handb Exp Pharmacol 215:57–76. doi: 10.1007/978–3–7091-1368-4_3
Becker KA, Tummler B, Gulbins E, Grassme H (2010) Accumulation of ceramide in the trachea and intestine of cystic fibrosis mice causes inflammation and cell death. Biochem Biophys Res Commun 403(3–4):368–374. doi:10.1016/j.bbrc.2010.11.038
Berry KA, Li B, Reynolds SD, Barkley RM, Gijon MA, Hankin JA, Henson PM, Murphy RC (2011) MALDI imaging MS of phospholipids in the mouse lung. J Lipid Res 52(8):1551–1560. doi:10.1194/jlr.M015750
Bragonzi A (2010) Murine models of acute and chronic lung infection with cystic fibrosis pathogens. Int J Med Microbiol 300(8):584–593. doi:10.1016/j.ijmm.2010.08.012
Bragonzi A, Paroni M, Nonis A, Cramer N, Montanari S, Rejman J, Di Serio C, Döring G, Tümmler B (2009) Pseudomonas aeruginosa microevolution during cystic fibrosis lung infection establishes clones with adapted virulence. Am J Respir Crit Care Med 180(2):138–145. doi:10.1164/rccm.200812-1943OC
Brice SE, Cowart LA (2011) Sphingolipid metabolism and analysis in metabolic disease. Adv Exp Med Biol 721:1–17. doi:10.1007/978-1-4614-0650-1_1
Caretti A, Bragonzi A, Facchini M, De Fino I, Riva C, Gasco P, Musicanti C, Casas J, Fabrias G, Ghidoni R, Signorelli P (2014) Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis. Biochim Biophys Acta 1840(1):586–594. doi:10.1016/j.bbagen.2013.10.018
Cowart LA, Szulc Z, Bielawska A, Hannun YA (2002) Structural determinants of sphingolipid recognition by commercially available anti-ceramide antibodies. JLipid Res 43(12):2042–2048
Fabelo N, Martín V, Santpere G, Marín R, Torrent L, Ferrer I, Díaz M (2011) Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease. Mol Med 17(9–10):1107–1118. doi:10.2119/molmed
Fabrias G, Muñoz-Olaya J, Cingolani F, Signorelli P, Casas J, Gagliostro V, Ghidoni R (2012) Dihydroceramide desaturase and dihydrosphingolipids: debutant players in the sphingolipid arena. Prog Lipid Res 51(2):82–94. doi:10.1016/j.plipres.2011.12.002
Fiedorowicz A, Prokopiuk S, Zendzian-Piotrowska M, Chabowski A, Car H (2014) Sphingolipid profiles are altered in prefrontal cortex of rats under acute hyperglycemia. Neuroscience 256:282–291. doi:10.1016/j.neuroscience
Gómez-Muñoz A (2006) Ceramide 1-phosphate/ceramide, a switch between life and death. Biochim Biophys Acta 1758(12):2049–2056
Grassme H, Riethmuller J, Gulbins E (2013) Ceramide in cystic fibrosis. Handb Exp Pharmacol 216:265–274. doi: 10.1007/978–3–7091-1511-4_13
Hammad SM (2011) Blood sphingolipids in homeostasis and pathobiology. Adv Exp Med Biol 721:57–66. doi:10.1007/978-1-4614-0650-1_4
Huwiler A, Johansen B, Skarstad A, Pfeilschifter J (2001) Ceramide binds to the CaLB domain of cytosolic phospholipase A2 and facilitates its membrane docking and arachidonic acid release. FASEB J 15(1):7–9
Karahatay S, Thomas K, Koybasi S, Senkal CE, Elojeimy S, Liu X, Bielawski J, Day TA, Gillespie MB, Sinha D, Norris JS, Hannun YA, Ogretmen B (2007) Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis. Cancer Lett 256(1):101–111
Kitatani K, Akiba S, Sato T (2004) Ceramide-induced enhancement of secretory phospholipase A2 expression via generation of reactive oxygen species in tumor necrosis factor-alpha-stimulated mesangial cells. Cell Signal 16(8):967–74
Maceyka M, Spiegel S (2014) Sphingolipid metabolites in inflammatory disease. Nature 510:58–67. doi:10.1038/nature13475
McAdam PR, Holmes A, Templeton KE, Fitzgerald JR (2011) Adaptive evolution of Staphylococcus aureus during chronic endobronchial infection of a cystic fibrosis patient. PLoS One 6(9):e24301. doi:10.1371/journal.pone.0024301
Panchal M, Gaudin M, Lazar AN, Salvati E, Rivals I, Ayciriex S, Dauphinot L, Dargère D, Auzeil N, Masserini M, Laprévote O, Duyckaerts C (2014) Ceramides and sphingomyelinases in senile plaques. Neurobiol Dis 65:193–201. doi:10.1016/j.nbd.2014.01.010
Petrache I, Petrusca DN (2013) The involvement of sphingolipids in chronic obstructive pulmonary diseases. Handb Exp Pharmacol 216:247–264. doi:10.1007/978-3-7091-1511-4_12
Riethmuller J, Anthonysamy J, Serra E, Schwab M, Doring M, Gulbins E (2009) Therapeutic efficacy and safety of amitriptyline in patients with cystic fibrosis. Cell Physiol Biochem 24(1–2):65–72. doi:10.1159/000227814
Sato H, Taketomi Y, Isogai Y, Masuda S, Kobayashi T, Yamamoto K, Murakami M (2009) Group III secreted phospholipase A2 transgenic mice spontaneously develop inflammation. Biochem J 421(1):17–27. doi: 10.1042/BJ20082429
Stremmel W, Merle U, Zahn A, Autschbach F, Hinz U, Ehehalt R (2005) Retarded release phosphatidylcholine benefits patients with chronic active ulcerative colitis. Gut 54(7):966–971
Takabe K, Paugh SW, Milstien S, Spiegel S (2008) “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev 60(2):181–195. doi:10.1124/pr.107.07113
Teichgraber V, Ulrich M, Endlich N, Riethmuller J, Wilker B, De Oliveira-Munding CC, van Heeckeren AM, Barr ML, von Kurthy G, Schmid KW, Weller M, Tummler B, Lang F, Grassme H, Doring G, Gulbins E (2008) Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med 14(4):382–391. doi:10.1038/nm1748
Treede I, Braun A, Sparla R, Kuhnel M, Giese T, Turner JR, Anes E, Kulaksiz H, Fullekrug J, Stremmel W, Griffiths G, Ehehalt E (2007) Anti-inflammatory effects of phosphatidylcholine. J Biol Chem 282:27155–27164
Ulrich M, Worlitzsch D, Viglio S, Siegmann N, Iadarola P, Shute JK, Geiser M, Pier GB, Friedel G, Barr ML, Schuster A, Meyer KC, Ratjen F, Bjarnsholt T, Gulbins E, Doring G (2010) Alveolar inflammation in cystic fibrosis. J Cyst Fibros 9(3):217–227. doi:10.1016/j.jcf.2010.03.001
Yoder M, Zhuge Y, Yuan Y, Holian O, Kuo S, van Breemen R, Thomas LL, Lum H (2014) Bioactive lysophosphatidylcholine 16:0 and 18:0 are elevated in lungs of asthmatic subjects. Allergy, Asthma Immunol Res 6(1):61–65. doi:10.4168/aair.2014.6.1.61
Acknowledgments
The authors thank B. Tümmler (Klinische Forschergruppe, Medizinische Hochschule Hannover, Germany) for supplying the P. aeruginosa AA2 clinical strain and G. Pier for the rabbit anti-serum specific for P. aeruginosa. Financial and administrative support from Italian Cystic Fibrosis Research Fundation is acknowledged (FFC #-11 2016). The University of Milan PhD program in Molecular Medicine is acknowledged. Fondazione Roma is acknowledged for the financial support in myriocin-SLN and post-doctoral fellowship.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Supplementary figure 1
(DOCX 103 kb)
Supplementary figure 2
(DOCX 88 kb)
Supplementary figure 3
(DOCX 72 kb)
Supplementary figure 4
(DOCX 93 kb)
Supplementary figure 5
(DOCX 80 kb)
Supplementary figure 6
(DOCX 93 kb)
Supplementary figure 7
(DOCX 98 kb)
Supplementary figure 8
(DOCX 93 kb)
Supplementary figure 9
(DOCX 94 kb)
Supplementary figure 10
(DOCX 75 kb)
Rights and permissions
About this article
Cite this article
Caretti, A., Vasso, M., Bonezzi, F.T. et al. Myriocin treatment of CF lung infection and inflammation: complex analyses for enigmatic lipids. Naunyn-Schmiedeberg's Arch Pharmacol 390, 775–790 (2017). https://doi.org/10.1007/s00210-017-1373-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-017-1373-4