Neutrophil elastase and acute lung injury: Prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics

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Abstract
To review the evidence and rationale that suggest that neutrophil elastase (NE) may contribute to the development of acute lung injury (ALI) and the acute respiratory distress syndrome. To review selected preliminary data regarding the effectiveness of NE inhibition in animals, in in vitro models, and in patients with ALI. The published literature and observations provided by Ono Pharmaceutical and Eli Lilly investigators and their colleagues. Taken en toto, the data suggest that NE could contribute to ALI and endothelial cell injury that is relevant to ALI. Moreover, the toxic effects of NE are greatly enhanced by increased oxidative stress, which commonly occurs in patients with ALI. In addition to neutrophils, xanthine oxidase, a constituent of endothelial cells, is a potential source of oxidative stress in ALI; xanthine oxidase-derived oxidants enhance NE toxicity in in vivo, isolated lung, and in vitro endothelial cell test systems. Not surprisingly, endogenous nonoxidatively sensitive NE inhibitors (e.g., eglin C) are more effective in combating the detrimental effects of NE than oxidatively sensitive NE inhibitors (e.g., α-1-proteinase inhibitor). In addition, a synthetic NE inhibitor, sivelestat (ONO-5046 and LY544349), is effective in reducing measures of inflammation and injury in multiple animal models of ALI. In a trial of ALI patients with systemic inflammatory response syndrome, conducted in Japan by Ono Pharmaceutical scientists, sivelestat treatment improved the investigator assessment of global improvement and the percentages of patients who were removed from ventilators and transferred out of the intensive care unit. Further study of the role of NE inhibition as a treatment for ALI is warranted. Additional clinical and preclinical studies with sivelestat and various other NE inhibitors should not only clarify the clinical potential of this intervention strategy, but also better define the activities of NE in inflammatory disorders such as ALI and multiple organ failure.