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Protective effect of ethyl-3-(3-dimethyl aminopropyl)urea dihydrochloride (EDU) against LPS-induced death in mice

Tetsuya Matsumoto¹, Edward E.S. Nieuwenhuis^2,3, Ronald L. Cisneros¹, Begoña Ruiz-Perez¹, Keizo Yamaguchi⁴, Richard S. Blumberg² and Andrew B. Onderdonk¹

^1,2Channing Laboratory, Department of Pathology¹ and Gastroenterology Division², Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA ³Laboratory of Pediatrics, Department of Pediatric Gastroenterology, Erasmus MC, Rotterdam, the Netherlands ⁴Department of Microbiology, Toho University School of Medicine, Tokyo, Japan

Correspondence Andrew B. Onderdonk onderdonk{at}aol.com

Received July 11, 2003
Accepted October 21, 2003

Evaluation of anti-adhesive gels and bioresorbable films in animal models of intra-abdominal infection has shown that a product of the cross-linking reaction between hyaluronic acid (HA) and CM-cellulose, 1-ethyl-3-(3-dimethyl aminopropyl)urea dihydrochloride (EDU), has immunomodulatory properties. The effects of EDU were evaluated by using an endotoxin-induced shock mouse model. Pre-treatment of mice with EDU (50 mg kg^-1) in DMSO resulted in a significant reduction in mortality following injection of LPS, compared to vehicle (DMSO) pre-treatment alone. Serum levels of TNF-, IL1ß and IFN- in EDU-treated mice were significantly lower than those in vehicle-treated mice. Nitric oxide (NO) concentrations in the sera of mice after inoculation with LPS were significantly lower in the EDU-treated group than in the vehicle-treated group at various time-points. In contrast, EDU pre-treatment was associated with an enhanced IL10 response after LPS injection, compared to vehicle pre-treatment alone. In vitro studies revealed that IL10 production by RAW 264.7 macrophages, elicited by LPS, was increased significantly when EDU was added to the culture medium. These results suggest that the protective effect of EDU during LPS-induced shock in mice is the result of inhibition of proinflammatory cytokines and NO production and an enhanced IL10 response.

These authors contributed equally to this work.

Abbreviations: EDC, 1-(3-dimethyl aminopropyl)-3-ethyl carbodiimide hydrochloride; EDU, ethyl-3-(3-dimethyl aminopropyl)urea dihydrochloride; HA, hyaluronic acid; IP, intraperitoneal; IV, intravenous.