PROTECTIVE EFFECTS OF AN APTAMER INHIBITOR OF NEUTROPHIL ELASTASE IN LUNG INFLAMMATORY INJURY

Neutrophils play an important part in the development of acute inflamm atory injury. Human neutrophils contain high levels of the serine prot ease elastase, which is stored in azurophilic granules and is secreted in response to inflammatory stimuli, Elastase is capable of degrading many components of extracellular matrix [1-4] and has cytotoxic effec ts on endothelial cells [5-7] and airway epithelial cells, Three types of endogenous protease inhibitors control the activity of neutrophil elastase, including alpha-1 protease inhibitor (alpha-1PI), alpha-2 ma croglobulin and secreted leukoproteinase inhibitor (SLPI) [8-10], A di sturbed balance between neutrophil elastase and these inhibitors has b een found in various acute clinical conditions (such as adult respirat ory syndrome and ischemia-reperfusion injury) and in chronic diseases, We investigated the effect of NX21909, a selected oligonucleotide (ap tamer) inhibitor of elastase, in an animal model of acute lung inflamm atory disease [11-14], This inhibitor was previously selected from a h ybrid library of randomized DNA and a small-molecule irreversible inhi bitor of elastase (a valine diphenyl ester phosphonate, Figure 1), by the blended SELEX process [15]. We show that NX21909 inhibits lung inj ury and neutrophil influx in a dose dependent manner, the first demons tration of efficacy by an aptamer in an animal disease model.