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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

Abstract

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.

Notes

Acknowledgments

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

References

  1. 1.
    Remick DG. (2007) Pathophysiology of sepsis. Am. J. Pathol. 170:1435–44.CrossRefGoogle Scholar
  2. 2.
    Howell G, Tisherman SA. (2006) Management of sepsis. Surg. Clin. North Am. 86:1523–39.CrossRefGoogle Scholar
  3. 3.
    Powers J, Jacobi J. (2006) Pharmacologic treatment related to severe sepsis. AACN. Adv. Crit. Care 17:423–32.PubMedGoogle Scholar
  4. 4.
    Jenkins I. (2006) Evidence-based sepsis therapy: a hospitalist perspective. J. Hosp. Med. 1:285–95.CrossRefGoogle Scholar
  5. 5.
    Bernard GR, et al. (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344:699–709.CrossRefGoogle Scholar
  6. 6.
    Martin GS, Mannino DM, Eaton S, Moss M. (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348:1546–54.CrossRefGoogle Scholar
  7. 7.
    Danai PA, Sinha S, Moss M, Haber MJ, Martin GS. (2007) Seasonal variation in the epidemiology of sepsis. Crit. Care Med. 35:410–5.CrossRefGoogle Scholar
  8. 8.
    Strehlow MC, Emond SD, Shapiro NI, Pelletier AJ, Camargo CA Jr. (2006) National study of emergency department visits for sepsis, 1992 to 2001. Ann. Emerg. Med. 48:326–31.CrossRefGoogle Scholar
  9. 9.
    Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29:1303–10.CrossRefGoogle Scholar
  10. 10.
    Kitamura K, et al. (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem. Biophys. Res. Commun. 192:553–60.CrossRefGoogle Scholar
  11. 11.
    Elsasser TH, et al. (1999) Adrenomedullin binding protein in the plasma of multiple species: characterization by radioligand blotting. Endocrinology 140:4908–11.CrossRefGoogle Scholar
  12. 12.
    Pio R, et al. (2001) Complement factor H is a serum binding protein for adrenomedullin. The resulting complex modulates the bioactivities of both partners. J. Biol. Chem. 276:12292–300.CrossRefGoogle Scholar
  13. 13.
    Zhou M, Ba ZF, Chaudry IH, Wang P. (2002) Adrenomedullin binding protein-1 modulates vascular responsiveness to adrenomedullin in late sepsis. Am. J. Physiol Regul. Integr. Comp. Physiol. 283:R553–60.CrossRefGoogle Scholar
  14. 14.
    Yang S, Zhou M, Chaudry IH, Wang P. (2002) Novel approach to prevent the transition from the hyperdynamic phase to the hypodynamic phase of sepsis: role of adrenomedullin and adrenomedullin binding protein-1. Ann. Surg. 236:625–33.CrossRefGoogle Scholar
  15. 15.
    Yang S, Zhou M, Fowler DE, Wang P. (2002) Mechanisms of the beneficial effect of adrenomedullin and adrenomedullin-binding protein-1 in sepsis: down-regulation of proinflammatory cytokines. Crit. Care Med. 30:2729–35.CrossRefGoogle Scholar
  16. 16.
    Dogan A, et al. (1997) Intravenous infusion of adrenomedullin and increase in regional cerebral blood flow and prevention of ischemic brain injury after middle cerebral artery occlusion in rats. J. Cereb. Blood Flow Metab. 17:19–25.CrossRefGoogle Scholar
  17. 17.
    Wu R, et al. (2007) Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats. Am. J. Respir. Crit. Care Med. 176:805–13.CrossRefGoogle Scholar
  18. 18.
    Cui X, Wu R, Zhou M, Simms HH, Wang P. (2004) Differential expression of cytochrome P450 isoforms in the lungs of septic animals. Crit. Care Med. 32:1186–91.CrossRefGoogle Scholar
  19. 19.
    Wu R, et al. (2007) Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve. Ann. Surg. 245:480–6.CrossRefGoogle Scholar
  20. 20.
    Fink MP. (1994) Effect of critical illness on microbial translocation and gastrointestinal mucosa permeability. Semin. Respir. Infect. 9:256–60.PubMedGoogle Scholar
  21. 21.
    Chavez AM, Menconi MJ, Hodin RA, Fink MP. (1999) Cytokine-induced intestinal epithelial hyperpermeability: role of nitric oxide. Crit Care Med. 27:2246–51.CrossRefGoogle Scholar
  22. 22.
    Yang R, et al. (2003) IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock and resuscitation in mice. Am J. Physiol. Gastrointest. Liver Physiol. 285:G621–29.CrossRefGoogle Scholar
  23. 23.
    Yang R, et al. (2006) Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock. Mol. Med. 12:105–14.CrossRefGoogle Scholar
  24. 24.
    Wu R, et al. (2008) Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia-reperfusion. PLoS. ONE. 3:e2026.CrossRefGoogle Scholar
  25. 25.
    Kitamura K, et al. (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem. Biophys. Res. Commun. 192:553–60.CrossRefGoogle Scholar
  26. 26.
    Samson WK. (1999) Adrenomedullin and the control of fluid and electrolyte homeostasis. Annu. Rev. Physiol. 61:363–89.CrossRefGoogle Scholar
  27. 27.
    Isumi Y, Kubo A, Katafuchi T, Kangawa K, Minamino N. (1999) Adrenomedullin suppresses interleukin-1β-induced tumor necrosis factor-α production in Swiss 3T3 cells. FEBS Lett. 463:110–4.CrossRefGoogle Scholar
  28. 28.
    Kubo A, et al. (1998) Production of adrenomedullin in macrophage cell line and peritoneal macrophage. J. Biol. Chem. 273:16730–8.CrossRefGoogle Scholar
  29. 29.
    Dackor R, Caron K. (2007) Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock. Peptides 28:2164–70.CrossRefGoogle Scholar
  30. 30.
    Ueda S, et al. (1999) Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome. Am. J. Respir. Crit Care Med. 160:132–6.CrossRefGoogle Scholar
  31. 31.
    Nishio K, et al. (1997) Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock. Crit. Care Med. 25:953–7.CrossRefGoogle Scholar
  32. 32.
    Wang P, Zhou M, Ba ZF, Cioffi WG, Chaudry IH. (1998) Up-regulation of a novel potent vasodilatory peptide adrenomedullin during polymicrobial sepsis. Shock 10:118–22.CrossRefGoogle Scholar
  33. 33.
    Fowler DE, et al. (2003) Adrenomedullin and adrenomedullin binding protein-1: their role in the septic response. J. Surg. Res. 109:175–81.CrossRefGoogle Scholar
  34. 34.
    Demberg T, Pollok-Kopp B, Gerke D, Gotze O, Schlaf G. (2002) Rat complement factor H: molecular cloning, sequencing and quantification with a newly established ELISA. Scand. J. Immunol. 56:149–60.CrossRefGoogle Scholar
  35. 35.
    Beltowski J, Jamroz A. (2004) Adrenomedullin: what we know 10 years since its discovery? Pol. J. Pharmacol. 56:5–27.Google Scholar
  36. 36.
    Wu R, Zhou M, Wang P. (2003) Adrenomedullin and adrenomedullin binding protein-1 downregulate TNF-alpha in macrophage cell line and rat Kupffer cells. Regul. Pept. 112:19–26.CrossRefGoogle Scholar
  37. 37.
    Miksa M, et al. (2007) Vasoactive hormone adrenomedullin and its binding protein: anti-inflammatory effects by up-regulating peroxisome proliferator-activated receptor-gamma. J. Immunol. 179:6263–72.CrossRefGoogle Scholar
  38. 38.
    Naked GM, et al. (2000) Deficiency of human complement factor I associated with lowered factor H. Clin. Immunol. 96:162–7.CrossRefGoogle Scholar
  39. 39.
    Cui Y, Ji Y, Wu R, Zhou M, Wang P. (2006) Adrenomedullin binding protein-1 is downregulated during polymicrobial sepsis in the rat. Int. J. Mol. Med. 17:925–9.PubMedGoogle Scholar
  40. 40.
    Friese MA, et al. (1999) FHL-1/reconectin and factor H: two human complement regulators which are encoded by the same gene are differently expressed and regulated. Mol. Immunol. 36:809–18.CrossRefGoogle Scholar
  41. 41.
    Schwaeble W, et al. (1987) Human complement factor H: expression of an additional truncated gene product of 43 kDa in human liver. Eur. J. Immunol. 17:1485–9.CrossRefGoogle Scholar
  42. 42.
    Luo W, Vik DP. (1999) Regulation of complement factor H in a human liver cell line by interferongamma. Scand. J. Immunol. 49:487–94.CrossRefGoogle Scholar
  43. 43.
    Haas PJ, van Strijp J. (2007) Anaphylatoxins: their role in bacterial infection and inflammation. Immunol. Res. 37:161–75.CrossRefGoogle Scholar
  44. 44.
    Hoesel LM, Gao H, Ward PA. (2006) New insights into cellular mechanisms during sepsis. Immunol. Res. 34:133–41.CrossRefGoogle Scholar
  45. 45.
    Hoesel LM, Niederbichler AD, Ward PA. (2007) Complement-related molecular events in sepsis leading to heart failure. Mol. Immunol. 44:95–102.CrossRefGoogle Scholar
  46. 46.
    Sakata J, et al. (1993) Molecular cloning and biological activities of rat adrenomedullin, a hypotensive peptide. Biochem. Biophys. Res. Commun. 195:921–7.CrossRefGoogle Scholar
  47. 47.
    Wu R, et al. (2008) Human vasoactive hormone adrenomedullin and its binding protein rescue experimental animals from shock. Peptides 29:1223–30.CrossRefGoogle Scholar

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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