17-DMAG Diminishes Hemorrhage-Induced Small Intestine Injury by Elevating Bcl-2 Protein and Inhibiting iNOS Pathway, TNF-alpha Increase, and Caspase-3 Activation

Abstract

Hemorrhage increases inducible nitric oxide synthase (iNOS) and depletes ATP levels in various tissues. Previous studies have shown that geldanamycin, an inducer of heat shock protein 70kDa (HSP-70) and inhibitor of iNOS, limits both processes. Reduction in NO production limits lipid peroxidation, apoptosome formation, and caspase-3 activation, thereby increasing cellular survival and reducing the sequelae of hemorrhage. The poor solubility of geldanamycin in aqueous solutions, however, limits its effectiveness as a drug. 17-DMAG is a water-soluble analog of geldanamycin that might have greater therapeutic utility. This study investigated the effectiveness of 17-DMAG at reducing hemorrhagic injury in mouse small intestine. Results In mice, the hemorrhage-induced iNOS increase correlated with increases in Kruppel-like factor 6 (KLF6) and NF-kB and a decrease in KLF4. As a result, increases in NO production and lipid peroxidation occurred. Moreover, hemorrhage also resulted in decreased Bcl-2 and increased TNF-a, IL-6, and IL-10 concentrations, p53 protein, caspase-3 activation, and cellular ATP depletion. A shortening and widening of villi in the small intestine was also observed. Treatment with 17-DMAG significantly reduced the hemorrhage-induced increases in iNOS protein, jejunal alteration, and TNF-a and IL-10 concentrations, but 17-DMAG did not affect the hemorrhageinduced increases in p53 and IL-6 concentration. 17-DMAG treatment by itself upregulated HSP-70, Bcl-2, and p53. Conclusion Since 17-DMAG is water soluble, bioactive, and not toxic, 17-DMAG may prove useful as a prophylactic drug for hemorrhage.

Open PDF

Document Details

Document Type
Technical Report
Publication Date
Jun 03, 2011
Accession Number
ADA544339

Entities

People

  • Joan T. Smith
  • Juliann G Kiang
  • Neil G. Agravante
  • Phillip D. Bowman

Organizations

  • Armed Forces Radiobiology Research Institute

Tags

DTIC Thesaurus Topics

  • Apoptosis
  • Aqueous Solutions
  • Biological Sciences
  • Biotechnology
  • Cardiovascular Physiological Phenomena
  • Cell Physiological Processes
  • Chemistry
  • Data Analysis
  • Hemorrhage
  • Inhibitors
  • Intestines
  • Measurement
  • Production
  • Proteins
  • Small Intestine
  • Transcription Factors
  • Water

Fields of Study

  • Biology
  • Medicine

Readers

  • Cellular and Molecular Pathways of Apoptosis.
  • Immunology and Pathology
  • Trauma Surgery or Emergency Medicine.