Effect of Cornuside on Experimental Sepsis

Abstract

This study was conducted to investigate the efficacy of cornuside, a secoiridoid glucoside compound, in cultured macrophages as well as in an experimental model of sepsis induced by cecal ligation and puncture (CLP) in rats. Cornuside was added to cultured macrophages at different concentrations, and all CLP rats were randomized to receive an intravenous injection of the corresponding drug followed by observation of its antisepsis effect. Our results showed that cornuside downregulated the levels of TNF-α, IL-6, and NO production in a dose-dependent manner in activated macrophages, while it upregulated the level of IL-10. Intravenous injection of cornuside or imipenem alone or in combination reduced CLP-induced lethality in rats after CLP. In addition, serum levels of TNF-α, IL-6, triggering receptor expressed on myeloid cells, and endotoxin were downregulated. On the other hand, the serum levels of IL-10 were upregulated. Decreased bacterial counts in blood, peritoneum, spleen, liver, and mesenteric lymph nodes and decreased myeloperoxidase in lung, liver, and small intestine also were found after cornuside injection. These data indicate that the antisepsis therapeutic effect of cornuside is mediated by decreased local and systemic levels of a wide spectrum of inflammatory mediators. This work provides first evidence for the clinic use of cornuside as a new immunomodulatory drug that has the capacity to inhibit the inflammatory response in sepsis.

Key words

cornuside - septic shock - triggering receptor expressed on myeloid cells - IL‐6 - IL‐10 - cecal ligation and puncture

References

• 1 Angus D C, Wax R S. Epidemiology of sepsis: an update.  Crit Care Med. 2001;  29 S109-S116
• 2 Cohen J. The immunopathogenesis of sepsis.  Nature. 2002;  420 885-891
• 3 Ching L L, Wen Y H, Ch L W, Hsu T K, Yen T L. Triggering receptor expressed on myeloid cells-1 in pleural effusions: A marker of inflammatory disease.  Resp Med. 2007;  101 903-909
• 4 Knapp S, Gibot S, de Vos A, Versteeg H H, Colonna M, van der Poll T. Cutting edge: expression patterns of surface and soluble triggering receptor expressed on myeloid cells-1 in human endotoxemia.  J Immunol. 2004;  173 7131-7134
• 5 Gibot S, Kolopp-Sarda M N, Béné M C, Bollaert P E, Lozniewski A, Mory F, Faure G C. A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis.  J Exp Med. 2004;  200 1419-1426
• 6 Bouchon A, Facchetti F, Weigand M A, Colonna M. TREM‐1 amplifies inflammation and is a crucial mediator of septic shock.  Nature. 2001;  410 1103-1107
• 7 Klesney-Tait J, Turnbull I R, Colonna M. The TREM receptor family and signal integration.  Nat Immunol. 2006;  7 1266-1273
• 8 Fortin C F, Lesur O, Fulop Jr T. Effects of TREM‐1 activation in human neutrophils: activation of signaling pathways, recruitment into lipid rafts and association with TLR4.  Int Immunol. 2007;  19 41-50
• 9 Kang D G, Moon M K, Lee A S, Kwon T O, Kim J S, Lee H S. Cornuside suppresses cytokine-induced proinflammatory and adhesion molecules in the human umbilical vein endothelial cells.  Biol Pharm Bull. 2007;  30 1796-1799
• 10 Xu H Q, Hao H P. Effects of iridoid total glycoside from Cornus officinalis on prevention of glomerular overexpression of transforming growth factor beta 1 and matrixes in an experimental diabetes model.  Biol Pharm Bull. 2004;  27 1014-1018
• 11 Chang J S, Chiang L C, Hsu F F, Lin C C. Chemoprevention against hepatocellular carcinoma of Cornus officinalis in vitro.  Am J Chin Med. 2004;  32 717-725
• 12 Zhao S P, Xue Z. Studies on the chemical constituents of Cornus officinalis Sieb et Zucc.  Yao Xue Xue Bao. 1992;  27 845-848
• 13 Yang S, Lim Y P, Zhou M, Salvemini P, Schwinn H, Josic D, Koo D J, Chaudry I H, Wang P. Administration of human inter-alphainhibitors maintains hemodynamic stability and improves survival during sepsis.  Crit Care Med. 2002;  30 617-622
• 14 Cirioni O, Giacometti A, Ghiselli R, Bergnach C, Orlando F, Silvestri C, Moccheqiani F, Licci A, Skerlavaj B, Rocchi M, Saba V, Zanetti M, Scalise G. LL‐37 Protects rats against lethal sepsis caused by gram-negative bacteria.  Antimicrob Agents Chemother. 2006;  50 1674
• 15 Bradley P P, Christensen R D, Rothstein G. Cellular and extracellular myeloperoxidase in pyogenic inflammation.  J Invest Dermatol. 1982;  78 206-209
• 16 National Committee for Clinical Laboratory Standards .Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 5th edition: Approved Standard M7-A5. Wayne, PA, USA; NCCLS 2001
• 17 Wichterman K A, Baue A E, Chaudry I H. Sepsis and septic shock: a review of laboratory models and a proposal.  J Surg Res. 1980;  29 189-201
• 18 Colonna M, Fachetti F. TREM‐1: a new player in acute inflammatory responses.  J Infect Dis. 2003;  187 S397-S401
• 19 Gibot S, Massin F, Marcou M, Taylor V, Stidwill R, Wilson P. TREM‐1 promotes survival during septic shock in mice.  Eur J Immunol. 2007;  37 456-466
• 20 Mocellin S, Panelli M C, Wang E, Nagorsen D, Marincola F M. The dual role of IL‐10.  Trends Immunol. 2003;  24 36-43
• 21 Schneider C P, Schwacha M G, Chaudry I H. The role of interleukin-10 in the regulation of the systemic inflammatory response following trauma-hemorrhage.  Biochim Biophys Acta. 2004;  1689 22-32
• 22 Jaccard C, Troillet N, Harbarth S, Zanetti G. Prospective randomized comparison of imipenem-cilastatin and piperacillin-tazobactam in nosocomial pneumonia or peritonitis.  Antimicrob Agents Chemother. 1998;  42 2966-2972