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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 295/6/F1825    most recent 90442.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Leelahavanichkul, A. Articles by Star, R. A. Search for Related Content PubMed PubMed Citation Articles by Leelahavanichkul, A. Articles by Star, R. A.

Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice

Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Submitted 28 July 2008 ; accepted in final form 10 October 2008

We tested the anti-inflammatory agent methyl-2-acetamidoacrylate (M2AA), an ethyl pyruvate analog, in a cecal ligation-and-puncture (CLP) model of sepsis in CD-1 mice. M2AA administration at the time of CLP improved survival, renal function, kidney histology, liver injury, and splenocyte apoptosis, and lowered cytokine levels (TNF-, IL-6, IFN-, and IL-10). When M2AA treatment was delayed 6 h (but not 12 h), M2AA still significantly reduced kidney dysfunction, liver injury, splenocyte apoptosis, and cytokine levels. NF-B, a M2AA target, was transiently activated in spleen, peaking at 6 h; kidney and liver NF-B increased steadily with a plateau at 12–24 h. M2AA reduced NF-B activation in spleen at 6 h and in kidney and liver at 24 h. Splenectomy diminished the ability of M2AA to reduce cytokines, especially IL-6, but M2AA still decreased kidney and liver dysfunction, suggesting that splenic NF-B is not central to M2AA action. In contrast, beneficial effects of chloroquine on cytokines and organ damage were neutralized by splenectomy, demonstrating a spleen-specific chloroquine target. Because M2AA and chloroquine act differently, we tested this combination. Survival at 96 h was highest with combination therapy (57%) vs. chloroquine (38%), M2AA (47.6%), or vehicle (5%). The benefit of combination therapy over chloroquine or M2AA alone did not reach statistical significance, indicating potential mechanistic overlap. We conclude that the transient target(s) for M2AA responsible for the narrow 6-h therapeutic window is not splenic NF-B. Identifying this new target and downstream signaling pathways could lengthen the therapeutic window and improve combination therapy with chloroquine.

cecal ligation-puncture; spleen; apoptosis; nuclear factor-B; chloroquine