Molecular Medicine

, Volume 15, Issue 1–2, pp 28–33 | Cite as

Reversing Established Sepsis in Rats with Human Vasoactive Hormone Adrenomedullin and its Binding Protein

  • Rongqian Wu
  • Shinya Higuchi
  • Weifeng Dong
  • Youxin Ji
  • Mian Zhou
  • Corrado P. Marini
  • Thanjavur S. Ravikumar
  • Ping Wang
Research Article


We recently demonstrated that early administration of rat adrenomedullin (AM), a vasoactive peptide, in combination with its binding protein (human AMBP-1) produces various beneficial effects in sepsis. Human AM is a 52-amino acid peptide, but rat AM differs from human AM, having only 50 amino acid residues, with two amino acid deletions and six substitutions. It remains unknown whether a combination of human AM and human AMBP-1 (AM/AMBP-1) is also beneficial in sepsis and, if so, whether human AM/AMBP-1 reverses established sepsis in rats. To test the effects of human AM/AMBP-1, we induced sepsis in male adult rats by cecal ligation and puncture (CLP). At 10 h after CLP (i.e., severe sepsis), human AM (12–48 µg/kg body weight) was administered in combination with human AMBP-1 (40–160 µg/kg body weight). Vehicle-treated animals received a nonspecific human plasma protein (albumin). Blood and intestinal samples were collected at 20 h for various measurements. In additional groups of septic animals, the gangrenous cecum was surgically excised at 20 h after CLP The 10-day survival was recorded. Our results showed that tissue injury, as evidenced by increased levels of transaminases and lactate, was present at 20 h after CLP Proinflammatory cytokines tumor necrosis factor-α and interleukin-6 were significantly elevated. Gut barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and increased bacterial translocation to mesenteric lymph nodes, also occurred at 20 h after CLP Administration of human AM/AMBP-1 in established sepsis markedly attenuated tissue injury, reduced proinflammatory cytokine levels, ameliorated intestinal-barrier dysfunction, and improved the survival rate from 47% to 67%–80%. Thus, human AM/AMBP-1 can be further developed as a safe and effective therapy for patients with established sepsis.



This study was supported in part by National Institutes of Health grants.


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Copyright information

© The Feinstein Institute for Medical Research 2009

Authors and Affiliations

  • Rongqian Wu
    • 1
    • 2
  • Shinya Higuchi
    • 1
    • 2
  • Weifeng Dong
    • 1
    • 2
  • Youxin Ji
    • 1
    • 2
  • Mian Zhou
    • 1
    • 2
  • Corrado P. Marini
    • 1
    • 2
  • Thanjavur S. Ravikumar
    • 1
    • 2
  • Ping Wang
    • 1
    • 2
  1. 1.Laboratory of Surgical ResearchThe Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health SystemManhassetUSA
  2. 2.Department of SurgeryNorth Shore University Hospital and Long Island Jewish Medical CenterManhassetUSA

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