The role of sphingolipid metabolism disruption on lipopolysaccharide-induced lung injury in mice
| Autor: | Renata Tiemi Okuro, Mariana Nascimento Machado, Natalia Casquilho, Walter A. Zin, Alcendino Jardim-Neto, Georgia C. Atella, Alysson Roncally-Carvalho |
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| Rok vydání: | 2018 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine Pulmonary and Respiratory Medicine Ceramide Serine C-Palmitoyltransferase Lung injury Pharmacology Benzylidene Compounds Proinflammatory cytokine Mice 03 medical and health sciences chemistry.chemical_compound Myriocin medicine Animals Pharmacology (medical) Enzyme Inhibitors Lung Sphingolipids Aniline Compounds Chemistry Biochemistry (medical) Lung Injury respiratory system Sphingolipid Enzyme Activation Mice Inbred C57BL Phosphotransferases (Alcohol Group Acceptor) Sphingomyelin Phosphodiesterase 030104 developmental biology medicine.anatomical_structure Acid sphingomyelinase Oxidoreductases Sphingomyelin medicine.drug |
| Zdroj: | Pulmonary Pharmacology & Therapeutics. 50:100-110 |
| ISSN: | 1094-5539 |
| Popis: | Aim This study assessed pulmonary outcomes generated by inhibiting key enzymes of sphingolipid metabolism pathways related to ceramide synthesis in a murine model of lung injury induced by lipopolysaccharide (LPS). Methods C57BL/6 male adult mice received LPS intratracheally and the expressions of acid sphingomyelinase (ASM), neutral sphingomyelinase (NSM), serine palmitoyl transferase (SPT) and dihydroceramide synthase (DS) were assessed at 2, 4, 6, 12 and 24 h after LPS instillation in lung homogenate (n = 30). The pharmacological inhibition of ASM, NSM, SPT and DS were assayed in other mice groups by three different doses of desipramine, GW4869, myriocin and fumonisin, respectively (n = 90). Their most effective doses were administered intraperitoneally 1 or 2 h before LPS to different animal groups (n = 120). Mice underwent determination of pulmonary mechanics, lung histopathological aspects and apoptosis. Results The expression levels of the enzymes reached their peak at 2–4 h after LPS administration. ASM inhibition attenuated alveolar collapse and GW4869 decreased lung elastance, proinflammatory cytokines' levels and was more effective to improve alveolar collapse than desipramine. On the other hand, SPT blockage aggravated lung lesion and no effects it was observed with fumonisin. Moreover, simultaneous administration of inhibitors (desipramine + GW4869, myriocin + fumonisin and all inhibitors together) resulted in no changes. Conclusion Blockage of sphingomyelinases and the de novo pathways improved and aggravated lung injury, respectively, putatively suggesting specific targets to therapeutic strategies in LPS-induced lung injury. |
| Databáze: | OpenAIRE |
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