Submitted to: Journal of the National Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/25/2005
Publication Date: 7/12/2005
Citation: Schmelzer, K.R., Kubala, L., Newman, J.W., Kim, I., Eiserich, J.P., Hammock, B.D. Soluble epoxide hydrolase is a therapeutic target for acute inflammation. Journal of the National Academy of Sciences. 102,9772-9777, 2005. Interpretive Summary: Despite the extensive number of available anti-inflammatory medications, many people still suffer from their diseases or side effects of their medications. Therefore, developing new therapeutic strategies to treat inflammation remains an important endeavor. In this study, we demonstrate that the soluble epoxide hydrolase (sEH) is a key pharmacologic target for treating acute systemic inflammation. Small molecule inhibitors of this enzyme reduced multiple adverse effects (including death and tissue injury) in an acute inflammation model in the mouse. Moreover, these compounds decreased plasma inflammatory markers and promoted the formation of compounds involved in resolving inflammation. This work suggests that sEH inhibitors are promising new compounds for the treatment and management of acute inflammatory diseases.
Technical Abstract: As of 2004, >73 million people were prescribed anti-inflammatory medication. Despite the extensive number of current products, many people still suffer from their diseases or the pharmacological properties (side effects) of the medications. Therefore, developing therapeutic strategies to treat inflammation remains an important endeavor. Here, we demonstrate that the soluble epoxide hydrolase (sEH) is a key pharmacologic target for treating acute systemic inflammation. Lipopolysaccharide-induced mortality, systemic hypotension, and histologically evaluated tissue injury were substantially diminished by administration of urea-based, small-molecule inhibitors of sEH to C57BL_6 mice. Moreover, sEH inhibitors decreased plasma levels of proinflammatory cytokines and nitric oxide metabolites while promoting the formation of lipoxins, thus supporting inflammatory resolution. These data suggest that sEH inhibitors have therapeutic efficacy in the treatment and management of acute inflammatory diseases.