Long Term Objectives: To develop an effective treatment for important neutrophil elastase mediated disorders, such as the Adult Respiratory Distress Syndrome (ARDS) and emphysema. Immediate Specific Aims: To produce and purify the newly discovered neutrophil elastase inhibitor (NEI) from bacteria and to determine its efficacy in accepted models of ARDS and emphysema. The approaches will include experiments in in-vitro (cultured lung epithelial cell and isolated perfused lungs) and in-vivo (intact animal models) with the help of well recognized experts in the field of lung injury. Potential for Innovation and Application: Although Neutrophil Elastase appears to be an important mediator of many diseases, no effective anti-elastase therapies are now available. The newly discovered bacterial derived NEI has great potential to fill this need because it is a potent highly specific inhibitor of neutrophil elastase, resistant to inactivation by oxidants, and potentially active as a small, highly permeable molecule. These characteristics, and the possiblity forlarge scale production of the inhibitor by naturally growing bacteria make NEI a very attractive choice for development as a commercially valuable therapeutic agent for diseases mediated by neutrophil elastase.
