Much recent work points to inflammation as playing a vital role in sulfur mustard (SM) toxicity, and some efficacy in the treatment of SM injury has been observed with standard anti-inflammatory agents such as dexamethasone. Recent findings have profoundly implicated sphingolipids as critical agents in many inflammatory and immuno-modulatory processes, but this emerging understanding has, to date, not been applied to the treatment or diagnosis/prognosis of SM injury. Two important therapeutic targets in this lipid signaling inflammatory cascade are sphingosine-l-phosphate (S 1P) and neutral sphingomyelinase (nSMase). The over-all goal of the proposed research is to apply what has been discovered and developed at Medlyte with respect to these lipid-signaling agents to the discovery and development of products to treat and diagnose SM injury. In this regard, findings and methods associated with S1P and neutral sphingomyelinase are the core of the Medlyte technology. We intend to characterize and conclusively demonstrate the role of sphingolipids in the inflammatory process initiated by SM toxicity. Specifically, we will demonstrate that production of sphingolipids (primarily S 1P) mediates the inflammatory response that follows exposure to SM. We will initially employ a keratinocyte cell culture model to determine if the sphingolipid inflammatory mediators are participatory in cell's response to SM. We also intend to employ the well-established mouse ear vesicant model of cutaneous exposure using our in-house knockout mouse model that lacks key components of the sphingolipid signaling system. We anticipate that the KO mice will be more resistant to SM exposure. Anticipating the S1P will be the major lipid mediator in the inflammatory response, we will develop monoclonal antibodies against S 1P as a potential therapeutic in addition to our planned Phase II small molecule drug development program designed to limit sphingolipid production through blocking nSMase. ? Implication of sphingolipids as mediators of SM toxicity should provide an opportunity to develop more effective therapeutics, particularly the more serious pulmonary exposures. The anticipated success of Phase I will position us for a Phase II research plan to develop a sphingolipid-based therapeutic for patients exposed to SM ? ?
