Skip to main content
SpringerLink
Log in

Lactoferrin Protects Gut Mucosal Integrity During Endotoxemia Induced by Lipopolysaccharide in Mice

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The hypothesis that lactoferrin protects mice against lethal effects of bacterial lipopolysaccharide (LPS) is the subject of experimental investigations described in this article. Lipopolysaccharide is a powerful toxin produced by Gram negative bacteria that when injected into humans or experimental animals reproduce many of the pathophysiologic and immune responses caused by live bacteria. Lactoferrin administered intraperitoneally 1 hr prior to injection of LPS significantly enhanced the survival of mice, reducing LPS-induced mortality from 83.3% to 16.7%. Changes in locomotor and other behavioral activities resulting from LPS injection were not present in mice treated with lactoferrin. Also, histological examination of intestine revealed remarkable resistance to injury produced by LPS if mice were pretreated with lactoferrin. Severe villus atrophy, edema and epithelial vacuolation were observed in LPS-treated animals but not in lactoferrin-treated counterparts. Electrophysiological parameters were used to assess secretory and absorptive functions in the small intestine. In mice treated with LPS, transmural electrical resistance was reduced and absorption of glucose was increased. Lactoferrin treatment had no significant influence on basal electrophysiological correlates of net ion secretion or glucose absorption nor on changes induced by LPS. Collectively, these results suggest that lactoferrin attenuates the lethal effect of LPS and modulates behavioral and histopathological sequela of endotoxemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. REITER, B. 1983. The biological significance of lactoferrin. Intern. J. Tissue Reactions. 5:87-96.

    Google Scholar 

  2. SANCHEZ, L., M. CALVO, and J. H. BROCK. 1992. Biological role of lactoferrin. Arch. Dis. Child. 67:657-661.

    Google Scholar 

  3. LONNERDAL, B., and S. IYER. 1995. Lactoferrin: molecular structure and biological function. Annu. Rev. Nutr. 15:93-110.

    Google Scholar 

  4. BROCK, J. 1995. Lactoferrin: a multifunctional immunoregulatory protein? Immunol Today. 16:417-419.

    Google Scholar 

  5. BRITIGAN, B., J. S. SERODY, and M. S. COHEN. 1994. The role of lactoferrin as an anti-inflammatory molecule. In: Lactoferrin: Structure and Function. Ed. T. W. Hutchens et al., Plenum Press, New York. 143-155.

    Google Scholar 

  6. BULLEN, J. J. 1981. The significance of iron in infection. Rev. Infect. Dis. 3:1127-1138.

    Google Scholar 

  7. TOMITA, M., W. BELLAMY, M. TAKASE, K. YAMAUCHI, H. WAKABAYASHI, and K. KAWASE, 1991. Potent antibacterial peptides generated by pepsin digestion of bovine lactoferrin. J. Dairy Sci. 74:4137-4142.

    Google Scholar 

  8. BELLAMY, W., M. TAKASE, K. YAMAUCHI, H. WAKABAYASHI, K. KAWASE, and M. TOMITA. 1992. Identification of the bactericidal domain of lactoferrin. Biochim. Biophys. Acta. 1121:130-136.

    Google Scholar 

  9. SAWATZKI, G., and I. N. RICH. 1989. Lactoferrin stimulates colony stimulating factor production in vitro and in vivo. Blood Cells 15:371-385.

    Google Scholar 

  10. ZIMECKI, M., and M. MACHNICKI. 1994. Lactoferrin inhibits the effector phase of delayed type hypersensitivity to sheep erythrocytes and inflammatory reactions to M. bovis (BCG). Arch. Immunol. Ther. Exp. 42:171-177.

    Google Scholar 

  11. ZIMECKI, M., J. MAZURIER, M. MACHNICKI, Z. WIECZOREK, J. MONTREUIL, and G. SPIK. 1991. Immunostimulatory activity of lactotransferrin and maturation of CD4-CD8-thymocytes. Immunol. Lett. 30:119-124.

    Google Scholar 

  12. ZIMECKI, M., J. MAZURIER, G. SPIK, and J. A. KAPP. 1995. Human lactoferrin induces phenotypic and functional changes in splenic mouse B cells. Immunology 86:112-127.

    Google Scholar 

  13. ZIMECKI, M., J. MAZURIER, G. SPIK and J. A. KAPP. 1996. Lactoferrin inhibits proliferative response and cytokine production by TH1 but not TH2 cells. Arch. Immunol. Ther. Exp. 44:51-56.

    Google Scholar 

  14. SORIMACHI, K., K. AKIMOTO, Y. HATTORI, T. IEIRI, and A. NIWA. 1997. Activation of macrophages by lactoferrin: secretion of TNFa, IL-8 and NO. Biochem. Mol. Biol. Internat. 43:79-87.

    Google Scholar 

  15. MIYAZAWA, K., C. MANTEL, L. LU, D. C. MORRISON, H. E. BROXMEYER. Lactoferrin-lipopolysaccharide interactions. Effect on lactoferrin binding to monocyte /macrophage-differentiated HL-60 cells. J. Immunol. 1991;146:723-729.

    Google Scholar 

  16. CROUCH, S. P. M., K. J. SLATER, and J. FLETCHER. 1992. Regulation of cytokine release from mononuclear cells by the iron-binding protein lactoferrin. Blood 80:235-240.

    Google Scholar 

  17. ELASS-ROCHARD, E., A. ROSEANU, D. LEGRAND, M. TRIF, V. SALMON, C. MOTAS, J. MONTREUIL, and G. SPIK. 1995. Lactoferrin lipopolysaccharide interaction: involvement of the 28-34 loop region of human lactoferrin in the high-affinity binding to Escherichia coli 055B5 lipopolysaccharide. Biochem. J. 312:839-845.

    Google Scholar 

  18. ELASS-ROCHARD, E., D. LEGRAND, V. SALMON, A. ROSEANU, M. TRIF, P. S. TOBIAS, J. MAZURIER, and G. SPIK. 1998. Lactoferrin inhibits the endotoxin interaction with CD14 by competition with the lipopolysaccharide-binding protein. Infect. Immun. 66:486-491.

    Google Scholar 

  19. COHEN, M. S., J. MAO, G. T. RASMUSSEN, J. S. SERODY, and B. BRITIGAN, 1992. Interaction of lactoferrin and lipopolysaccharide (LPS): Effects on the antioxidant property of lactoferrin and the ability of LPS to prime human neutrophils for enhanced superoxide formation. J. Infect. Dis. 166:1375-1378.

    Google Scholar 

  20. WANG, D., K. M. PABST, Y. AIDA and M. J. PABST. 1995. Lipopolysaccharide-inactivating activity of neutrophils is due to lactoferrin. J. Leuk. Biol. 57:865-874.

    Google Scholar 

  21. MACHNICKI, M., M. ZIMECKI and T. ZAGULSKI. 1993. Lactoferrin regulates the release of tumor necrosis factor alpha and interleukin 6 in vivo. Int. J. Exp. Path. 74:433-439.

    Google Scholar 

  22. ZAGULSKI, T., P. LIPINSKI, A. ZAGULSKA, S. BRONIEK, and Z. JARZABEK. 1989. Lactoferrin can protect mice against lethal dose of Escherichia coli in experimental infection in vivo. Br. J. Exp. Path. 70:697-704.

    Google Scholar 

  23. LEE, W. J., J. L. FARMER, M. HILTY, and Y. B. KIM. 1998. The protective effects of lactoferrin feeding against endotoxin lethal shock in germfree piglets. Infect. Immun. 66:1421-1426.

    Google Scholar 

  24. BULLICK, G. R., R. A. FRIZZELL, and G. A. CASTRO. 1998. Trichinella spiralis: Rapid, Immunologically influenced Reduction of intestinal, Sodium-coupled sugar transport in rat. Experimental Parasitology 57:104-109.

    Google Scholar 

  25. DEITCH, E. A., and R. BERG. 1987. Endotoxin promotes the translocation of bacteria from the gut. Arch. Surg. 122:185-190.

    Google Scholar 

  26. DEITCH, E. A., and R. BERG, 1987. Endotoxin but not malnutrition promotes bacterial translocation in the gut flora in burn mice. J. Trauma., 27:161-166.

    Google Scholar 

  27. MAINOUS, M. R., W. ERTEL, I. H. CHAUDRY, and E. A. DEITCH. 1995. The gut: a cytokinegenerating organ in systemic inflammation? Shock 4:193-199.

    Google Scholar 

  28. DEITCH, E. A., D. XU, L. FRANKO, A. AYALA, and I. H. CHAUDRY. 1994. Evidence favoring the role of the gut as a cytokine-generating organ in rats subjected to hemorrhagic shock. Shock. 1:141-145.

    Google Scholar 

  29. DEITCH, E. A. 1992. Multiple organ failure: Pathophysiology and potential future therapy. Ann. Surg. 216:117-134.

    Google Scholar 

  30. BONE, R. C. 1991 The pathogenesis of sepsis. Ann. Int. Med. 115:457-469.

    Google Scholar 

  31. DEMARIA, E., and J. M. DALTON. 1997. Bacterial translocation and the release of endotoxin and cytokines following trauma. In: Cytokines in Trauma and Hemorrhage, Sugerman et al. editors. Chapman and Hall 43-61.

  32. TERAGUCHI, S., K. SHIN, T. OGATA, M. KINGAKU, A. KAINO, H. MIYAUCHI, Y. FUKUWATARI, and S. SHIMAMURA. 1995. Orally administered bovine lactoferrin inhibits bacterial translocation in mice fed bovine milk. Appl. Env. Microbiol. 61:4131-4144.

    Google Scholar 

  33. TERAGUCHI, S., K. SHIN, K. OZAWA, S. NAKAMURA, Y. FUKUWATARI, S. TSUYUKI, H. NAMIHIRA, and S. SHIMAMURA. 1995. Bacteriostatic effect of orally administered bovine lactoferrin on proliferation of Clostridium species in the gut of mice fed bovine milk. Appl. Env. Microbiol. 61:501-506.

    Google Scholar 

  34. MYERS, I., and D. JOHNSON. 1998. The nonspecific inflammatory response to injury. Can. J. Anaesth. 45:871-879.

    Google Scholar 

  35. STOGAUS, R., and M. G. KING. 1995. Is oral levamisole immunostimulation in rats mediated by reduced levels of free plasma corticosterone? Int. J. Immunopharmac. 17:635-640.

    Google Scholar 

  36. SYMOENS, J., and M. ROSENTHAL. 1977. Levamisol in the modulation of the immune response: the current experimental and clinical state. J. Reticuloendoth. Soc. 21:175-184.

    Google Scholar 

  37. ZIMECKI, M., A. WLASZCZYK, P. CHENEAU, A. S. BRUNEL, J. MAZURIER, G. SPIK, and A. KUBLER. 1998. Immunoregulatory effects of nutritional preparation containing bovine lactoferrin taken orally by healthy individuals. Arch. Immunol. Ther. Exp. 46:231-240.

    Google Scholar 

  38. BLANQUE, R., C. MEAKIN, S. MILLET, and C. R. GARDNER, 1996. Hypothermia as an indicator of the acute effects of lipopolysaccharides: comparison with serum levels of IL-1b, IL-6 and TNFa. Gen. Pharmac. 27:973-977.

    Google Scholar 

  39. KOZAK, W., H. ZHENG, C. A. CONN, D. SOSZYNSKI, L. X. T. VAN DER PLOEG, and M. J. KLUGER. 1995. Thermal and behavioral effects of lipopolysaccharide and influenza in interleukin-1bdeficient mice. Am. J. Physiol. 269:R969-R977.

    Google Scholar 

  40. KOZAK, W., C. A. CONN, J. J. KLIR, G. H. W. WONG, and M. J. KLUGER. 1995. TNF soluble receptor and antiserum against TNF enhance lipopolysaccharide fever in mice Am. J. Physiol. 269:R23-R29.

    Google Scholar 

  41. KOZAK, W., C. A. CONN, and M. J. KLUGER. 1994. Lipopolysaccharide induces fever and depresses locomotor activity in unrestrained mice Am. J. Physiol. 266:R125-135.

    Google Scholar 

  42. BLANQUE, R., C. MEAKIN, S. MILLER and C. R. GARDNER. 1995. Hypothermia as an indicator of the acute effects of lipopolysaccharides: Comparison with serum level of IL 1b, IL 6 and TNFa. Gen. Pharmac. 27:973-977.

    Google Scholar 

  43. KRUZEL, M. K., Y. HARARI, C. YING, A. C. CASTRO. 1998. Role of lactoferrin in development of systemic inflammatory response syndrome (SIRS). 2nd International Conference “Progress in Intensive Care Medicine” Wroclaw, Poland, May, pp. 11-12.

  44. KRUZEL, M., T. ZAGULSKI, and M. ZIMECKI. Lactoferrin and insult-induced metabolic imbalance. Proceedings, 4th International Conference on Lactoferrin: Structure, Function and Applications, K. Shimazaki editor, ICS. (In press.)

  45. ZAGULSKI, T., M. ZIMECKI and M. KRUZEL. Is nitric oxide involved in the protective effect against E. coli generated by lactoferrin in vivo? Proceedings, 4th International Conference on Lactoferrin: Structure, Function and Applications, K. Shimazaki editor ICS. (In press.)

Download references

Author information

Authors and Affiliations

  1. Department of Integrative Biology and Pharmacology, University of Texas, Houston Health Science Center, Texas, 77225

    Marian L. Kruzel, Yael Harari, Chung-Ying Chen & Gilbert A. Castro

Authors
  1. Marian L. Kruzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yael Harari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chung-Ying Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gilbert A. Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kruzel, M.L., Harari, Y., Chen, CY. et al. Lactoferrin Protects Gut Mucosal Integrity During Endotoxemia Induced by Lipopolysaccharide in Mice. Inflammation 24, 33–44 (2000). https://doi.org/10.1023/A:1006935908960

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006935908960

Keywords

Search

Navigation