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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2295-2301. Prepublished online as a Blood First Edition Paper on June 7, 2005; DOI 10.1182/blood-2004-10-4086. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-10-4086v1 106/7/2295    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wesche-Soldato, D. E. Articles by Ayala, A. Search for Related Content PubMed PubMed Citation Articles by Wesche-Soldato, D. E. Articles by Ayala, A. Related Collections Immunobiology Apoptosis Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY In vivo delivery of caspase-8 or Fas siRNA improves the survival of septic mice Doreen E. Wesche-Soldato, Chun-Shiang Chung, Joanne Lomas-Neira, Lesley A. Doughty, Stephen H. Gregory, and Alfred Ayala From the Division of Surgical Research, Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence; the Department of Pediatrics, Brown University School of Medicine, Providence; and the Department of Medicine, Brown University School of Medicine, Providence, RI. Although studies have shown increased evidence of death receptor-driven apoptosis in intestinal lymphoid cells, splenocytes, and the liver following the onset of polymicrobial sepsis, little is known about the mediators controlling this process or their pathologic contribution. We therefore attempted to test the hypothesis that the hydrodynamic administration of small interfering RNA (siRNA) against the death receptor, Fas or caspase-8, should attenuate the onset of morbidity and mortality seen in sepsis, as produced by cecal ligation and puncture (CLP). We initially show that in vivo administration of green fluorescent protein (GFP) siRNA in GFP transgenic mice results in a decrease in GFP fluorescence in most tissues. Subsequently, we also found that treating septic nontransgenic mice with siRNA targeting Fas or caspase-8 but not GFP (used as a control here) decreased the mRNA, in a sustained fashion up to 10 days, and protein expression of Fas and caspase-8, respectively. In addition, transferase-mediated dUTP (deoxyuridine triphosphate) nick end labeling (TUNEL) and active caspase-3 analyses revealed a decrease in apoptosis in the liver and spleen but not the thymus following siRNA treatment. Indices of liver damage were also decreased. Finally, the injection of Fas or caspase-8 given not only 30 minutes but up to 12 hours after CLP significantly improved the survival of septic mice. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Guo, Z. Song, M. Li, Q. Wu, D. Wang, H. Feng, P. Bernard, A. Daugherty, B. Huang, and X.-A. Li Scavenger Receptor BI Protects against Septic Death through Its Role in Modulating Inflammatory Response J. Biol. Chem., July 24, 2009; 284(30): 19826 - 19834. [Abstract] [Full Text] [PDF] N. Matsuda, S. Yamamoto, K.-i. Takano, S.-i. Kageyama, Y. Kurobe, Y. Yoshihara, Y. Takano, and Y. Hattori Silencing of Fas-associated Death Domain Protects Mice from Septic Lung Inflammation and Apoptosis Am. J. Respir. Crit. Care Med., May 1, 2009; 179(9): 806 - 815. [Abstract] [Full Text] [PDF] M. Lamkanfi, L. O. Moreira, P. Makena, D. C. J. Spierings, K. Boyd, P. J. Murray, D. R. Green, and T.-D. 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Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1050 - F1058. [Abstract] [Full Text] [PDF] J. Kim, Y. Shao, S. Y. Kim, S. Kim, H. K. Song, J. H. Jeon, H. W. Suh, J. W. Chung, S. R. Yoon, Y. S. Kim, et al. Hypoxia-induced IL-18 Increases Hypoxia-inducible Factor-1{alpha} Expression through a Rac1-dependent NF-{kappa}B Pathway Mol. Biol. Cell, February 1, 2008; 19(2): 433 - 444. [Abstract] [Full Text] [PDF] P. O. Scumpia, M. J. Delano, K. M. Kelly-Scumpia, J. S. Weinstein, J. L. Wynn, R. D. Winfield, C. Xia, C. S. Chung, A. Ayala, M. A. Atkinson, et al. Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis Blood, November 15, 2007; 110(10): 3673 - 3681. [Abstract] [Full Text] [PDF] N. Matsuda, Y. Takano, S.-i. Kageyama, N. Hatakeyama, K. Shakunaga, I. Kitajima, M. Yamazaki, and Y. 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