Effect of the sphingolipid synthesis inhibitor, myriocin, in a murine pulmonary inflammation model

Abstract Effect of the sphingolipid synthesis inhibitor, myriocin, in a murine pulmonary inflammation model Sphingolipids are signaling molecules involved in many aspects of cell function. Therapeutic modulation of the sphingolipid pathway is a potential approach to manage inflammation. Myriocin is a naturally occurring fungal metabolite that inhibits serine palmitoyltransferase (SPT), a vital enzyme in sphingolipid biosynthesis, and has been shown to have immunosuppressive properties. Using a murine acute pulmonary inflammation model as a surrogate inflammatory disease model, we evaluated the immune-modulatory effects of myriocin. Myriocin was administered at 0.3mg/kg, i.p., shortly after LPS challenge. Cellular infiltration into the lungs 24hrs and 48hrs after LPS challenge was significantly inhibited by myriocin. Macrophage, neutrophil, and lymphocyte numbers in the bronchoalveolar lavage fluid (BALf) were all significantly reduced by myriocin treatment as compared to the vehicle control group. Plasma ceramide levels were reduced 24hrs after myriocin treatment. There was no effect of myriocin on the pro-inflammatory cytokine TNFα, or chemokines KC and MIP-2 in the BALf. However, myriocin inhibited MCP-1 induced migration activity of BALf macrophages. These data provide support for the therapeutic modulation of the sphingolipid pathway as a strategy to suppress inflammation.