Tissue Hypoxia During Bacterial Sepsis is Attenuated by PR-39, an Antibacterial Peptide

  • Philip E. James
  • Melanie Madhani
  • Chris Ross
  • Linda Klei
  • Aaron Barchowsky
  • Harold M. Swartz
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 530)


Endotoxin (a lipopolysaccharide (LPS) component of the Gram negative bacterial cell wall) induces sepsis in laboratory animals and is the cause of septic shock in patients. Tissues often develop necrotic regions, particularly in kidney and liver, thought to be directly the result of endotoxin-induced release of nitric oxide (NO). These studies investigated the potential of PR-39, an antibacterial peptide, as an alternative treatment for sepsis. Our rationale for these experiments was based on the knowledge that PR-39 inhibits the superoxide-producing NADH/NADPH-oxidase system, and also inhibits NOS. In a mouse model of sepsis, we carried out EPR measurements of liver pO2 and NO simultaneously in vivo. Physiological parameters were also measured in these animals (blood pressure, heart rate). NO levels in blood were measured by EPR analysis of red blood cell nitrosyl-hemoglobin. We found PR-39 alleviated endotoxin-induced liver hypoxia 6 hrs after treatment. Tissue NO was higher in the PR-39+LPS group compared to LPS alone. Circulating levels of NO were the same in these groups. Taken together, these results suggest PR-39 is effective in improving survival following a septic episode. The exact mechanism is unclear, but increased NO as a result of decreased superoxide production seems to play an important role in alleviating tissue hypoxia.


Nitric Oxide Nitric Oxide Mean Arterial Blood Pressure Antibacterial Peptide Bacterial Sepsis 
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  1. 1.
    Cobb, J.P. and Danner, R.L. Nitric oxide and septic shock. JAMA 1996;275:1192–1196.PubMedCrossRefGoogle Scholar
  2. 2.
    Wright, C.E., Rees, D.D. and Moncada, S. Protective and pathological roles of nitric oxide in endotoxic shock. Cariovascular Research 1992; 26:48–57.CrossRefGoogle Scholar
  3. 3.
    Nathan, C.F., Stuehr, D.J. Does endothelium-derived nitric oxide have a role in cytokine-induced hypotension? J Natl Cancer Inst 1990; 82:726–728.PubMedCrossRefGoogle Scholar
  4. 4.
    Nathan, C., Xie, Q-W. Nitric oxide synthases: roles, tolls, controls. Cell 1994;78:915–918.PubMedCrossRefGoogle Scholar
  5. 5.
    Di Silvio, M., Nussler, A.K., Geller, D.A., and Billiar, T.R. A role for nitric oxide in liver inflammation and infection. In:Nitric Oxide: Principles and Actions (Lancaster, J. Jr., ed), Academic Press, 1996; 219–236.Google Scholar
  6. 6.
    Agerbeth, B., Lee, J., Bergman, T., Carlquist, M., Boman, H. G., Mutt, V., and Jomvall, H.: Amino acid sequence of PR39 — Isolation from pig intestine of a new member of the family of proline-argine-rich antibacterial peptides. European Journal Biochemistry. 1991;202: 849–854.CrossRefGoogle Scholar
  7. 7.
    Shi, J., Ross, C.R., Chengappa, M.M., and Blecha, F. Identification of a proline-rich antibacterial peptide from neutrophils that is analogous to PR-39, and antibacterial peptide from the small intestine. J Leukocyte Biol 1994; 56:807–811.PubMedGoogle Scholar
  8. 8.
    Boman, H. G., Agerbeth, B., and Boman, A.: Mechanism of action on Escherichia coli of cecropin P1 and PR39, two antibacterial peptides from pig intestine. Infection and Immunity. Biochemical and Biophysical research communication. 1993;61:29782984.Google Scholar
  9. 9.
    Shi, J., Ross, C. R, Leto, T. L, and Blecha, F.: PR29, a proline-rich antibacterial peptide that inhibits phagocyte NADPH oxidase activity by binding to Src homolgy 3 domains of p47phox. Preoceedings National Academy of Science, USA.1996; 93:6014–6018.CrossRefGoogle Scholar
  10. 10.
    Huang, H., Ross, C. R, and Blecha, F.: Chemoattractant properties of PR39, a neutrophil antibacterial peptide. Journal of Leukocytes Biology 1997;61:624–628.Google Scholar
  11. 11.
    Gallo, R. L, Ono, M., Povsic, T., Page, C., Eriksson, E.: Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antibacterial peptide from wounds. Proceedings National Academy of Science, USA 1994;91:11035–11039.CrossRefGoogle Scholar
  12. 12.
    Korthuis, R.J., Gute, D.C., Blecha, F., Ross, C.R. Pr-39, a proline/arginine-rich antimicrobial peptide, prevents postischemic microvascular dysfunction. Am J Physiol 1999;277:H 1007-H 1013.Google Scholar
  13. 13.
    James, P.E., Grinberg, O.Y., Goda, F., O’Hara, J.A., and Swartz, H.M. Gloxy: an oxygen-sensitive coal for accurate measurement of low oxygen tensionis in biological systems. Mag Res Med 1997; 38:48–58.CrossRefGoogle Scholar
  14. 14.
    James, P.E., Miyake, M., and Swartz, H.M. Simultaneous measurement of NO and po2 from tissue by in vivo EPR. Nitric oxide; Chemistry and Biology 1999; 3:292–301.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Philip E. James
    • 1
  • Melanie Madhani
    • 2
  • Chris Ross
    • 3
  • Linda Klei
    • 4
  • Aaron Barchowsky
    • 4
  • Harold M. Swartz
    • 2
  1. 1.Department of Cardiology, Wales Heart Research InstituteUniversity of Wales College of MedicineWalesUK
  2. 2.EPR Center, Radiology DepartmentDartmouth Medical SchoolUSA
  3. 3.Department of Anatomy and PhysiologyCollege of Vetinary Medicine, Kansas State UniversityUSA
  4. 4.Department of Pharmacology and ToxicologyDartmouth Medical SchoolUSA

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