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. 1995 Apr;95(4):1947–1952. doi: 10.1172/JCI117877

Protection against endotoxic shock by bactericidal/permeability-increasing protein in rats.

H Jin 1, R Yang 1, S Marsters 1, A Ashkenazi 1, S Bunting 1, M N Marra 1, R W Scott 1, J B Baker 1
PMCID: PMC295740  PMID: 7706502

Abstract

Bactericidal/permeability-increasing protein (BPI) is a neutrophil primary granule protein that inhibits effects of LPS in vitro. The current study examined the effects of BPI on hemodynamics, mortality, and circulating endotoxin and cytokines in conscious rats with endotoxic shock. Catheters were implanted into the right femoral artery and vein. 1 d later, human recombinant BPI (10 mg/kg) or vehicle was intravenously injected immediately, 30 min, or 2 h after intravenous injection of LPS (7.5 mg/kg). Mean arterial pressure (MAP) and heart rate were monitored and blood was collected before and after injection. BPI given immediately or 30 min after LPS prevented the LPS-induced reduction in MAP at 4-8 h and markedly reduced mortality. BPI given 2 h after LPS injection had no protective effect. BPI treated immediately after LPS reduced the circulating levels of endotoxin and IL-6 but increased the circulating levels of TNF. We propose that BPI exerts its protective effect through a TNF-independent mechanism, by inhibiting endotoxin-stimulated production of IL-6.

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Selected References

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  1. Ashkenazi A., Marsters S. A., Capon D. J., Chamow S. M., Figari I. S., Pennica D., Goeddel D. V., Palladino M. A., Smith D. H. Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10535–10539. doi: 10.1073/pnas.88.23.10535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
  3. Biber B., Schaefer C. F., Smolik M. J., Lerner M. R., Brackett D. J., Wilson M. F., Fagraeus L. Improved techniques for cardiovascular monitoring in rats as applied during endotoxemia. Am J Physiol. 1988 Jan;254(1 Pt 2):H181–H186. doi: 10.1152/ajpheart.1988.254.1.H181. [DOI] [PubMed] [Google Scholar]
  4. Block M. I., Berg M., McNamara M. J., Norton J. A., Fraker D. L., Alexander H. R. Passive immunization of mice against D factor blocks lethality and cytokine release during endotoxemia. J Exp Med. 1993 Sep 1;178(3):1085–1090. doi: 10.1084/jem.178.3.1085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bone R. C. The pathogenesis of sepsis. Ann Intern Med. 1991 Sep 15;115(6):457–469. doi: 10.7326/0003-4819-115-6-457. [DOI] [PubMed] [Google Scholar]
  6. Brackett D. J., Schaefer C. F., Tompkins P., Fagraeus L., Peters L. J., Wilson M. F. Evaluation of cardiac output, total peripheral vascular resistance, and plasma concentrations of vasopressin in the conscious, unrestrained rat during endotoxemia. Circ Shock. 1985;17(4):273–284. [PubMed] [Google Scholar]
  7. Brakenhoff J. P., de Groot E. R., Evers R. F., Pannekoek H., Aarden L. A. Molecular cloning and expression of hybridoma growth factor in Escherichia coli. J Immunol. 1987 Dec 15;139(12):4116–4121. [PubMed] [Google Scholar]
  8. Brandtzaeg P., Kierulf P., Gaustad P., Skulberg A., Bruun J. N., Halvorsen S., Sørensen E. Plasma endotoxin as a predictor of multiple organ failure and death in systemic meningococcal disease. J Infect Dis. 1989 Feb;159(2):195–204. doi: 10.1093/infdis/159.2.195. [DOI] [PubMed] [Google Scholar]
  9. Creasey A. A., Chang A. C., Feigen L., Wün T. C., Taylor F. B., Jr, Hinshaw L. B. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest. 1993 Jun;91(6):2850–2860. doi: 10.1172/JCI116529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Debets J. M., Kampmeijer R., van der Linden M. P., Buurman W. A., van der Linden C. J. Plasma tumor necrosis factor and mortality in critically ill septic patients. Crit Care Med. 1989 Jun;17(6):489–494. doi: 10.1097/00003246-198906000-00001. [DOI] [PubMed] [Google Scholar]
  11. Duma R. J. Gram-negative bacillary infections. Pathogenic and pathophysiologic correlates. Am J Med. 1985 Jun 7;78(6A):154–164. doi: 10.1016/0002-9343(85)90119-6. [DOI] [PubMed] [Google Scholar]
  12. Fisher C. J., Jr, Marra M. N., Palardy J. E., Marchbanks C. R., Scott R. W., Opal S. M. Human neutrophil bactericidal/permeability-increasing protein reduces mortality rate from endotoxin challenge: a placebo-controlled study. Crit Care Med. 1994 Apr;22(4):553–558. doi: 10.1097/00003246-199404000-00008. [DOI] [PubMed] [Google Scholar]
  13. Girardin E., Grau G. E., Dayer J. M., Roux-Lombard P., Lambert P. H. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med. 1988 Aug 18;319(7):397–400. doi: 10.1056/NEJM198808183190703. [DOI] [PubMed] [Google Scholar]
  14. Green E. M., Adams H. R. New perspectives in circulatory shock: pathophysiologic mediators of the mammalian response to endotoxemia and sepsis. J Am Vet Med Assoc. 1992 Jun 15;200(12):1834–1841. [PubMed] [Google Scholar]
  15. Hack C. E., De Groot E. R., Felt-Bersma R. J., Nuijens J. H., Strack Van Schijndel R. J., Eerenberg-Belmer A. J., Thijs L. G., Aarden L. A. Increased plasma levels of interleukin-6 in sepsis. Blood. 1989 Oct;74(5):1704–1710. [PubMed] [Google Scholar]
  16. Harris M. C., Costarino A. T., Jr, Sullivan J. S., Dulkerian S., McCawley L., Corcoran L., Butler S., Kilpatrick L. Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. J Pediatr. 1994 Jan;124(1):105–111. doi: 10.1016/s0022-3476(94)70264-0. [DOI] [PubMed] [Google Scholar]
  17. Havell E. A., Sehgal P. B. Tumor necrosis factor-independent IL-6 production during murine listeriosis. J Immunol. 1991 Jan 15;146(2):756–761. [PubMed] [Google Scholar]
  18. Hitchcock P. J., Leive L., Mäkelä P. H., Rietschel E. T., Strittmatter W., Morrison D. C. Lipopolysaccharide nomenclature--past, present, and future. J Bacteriol. 1986 Jun;166(3):699–705. doi: 10.1128/jb.166.3.699-705.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kelly N. M., Cross A. S. Interleukin-6 is a better marker of lethality than tumor necrosis factor in endotoxin treated mice. FEMS Microbiol Immunol. 1992 Aug;4(6):317–322. doi: 10.1111/j.1574-6968.1992.tb05011.x. [DOI] [PubMed] [Google Scholar]
  20. Kreger B. E., Craven D. E., McCabe W. R. Gram-negative bacteremia. IV. Re-evaluation of clinical features and treatment in 612 patients. Am J Med. 1980 Mar;68(3):344–355. doi: 10.1016/0002-9343(80)90102-3. [DOI] [PubMed] [Google Scholar]
  21. Mannion B. A., Kalatzis E. S., Weiss J., Elsbach P. Preferential binding of the neutrophil cytoplasmic granule-derived bactericidal/permeability increasing protein to target bacteria. Implications and use as a means of purification. J Immunol. 1989 Apr 15;142(8):2807–2812. [PubMed] [Google Scholar]
  22. Marra M. N., Wilde C. G., Collins M. S., Snable J. L., Thornton M. B., Scott R. W. The role of bactericidal/permeability-increasing protein as a natural inhibitor of bacterial endotoxin. J Immunol. 1992 Jan 15;148(2):532–537. [PubMed] [Google Scholar]
  23. Marra M. N., Wilde C. G., Griffith J. E., Snable J. L., Scott R. W. Bactericidal/permeability-increasing protein has endotoxin-neutralizing activity. J Immunol. 1990 Jan 15;144(2):662–666. [PubMed] [Google Scholar]
  24. McNamara M. J., Norton J. A., Nauta R. J., Alexander H. R. Interleukin-1 receptor antibody (IL-1rab) protection and treatment against lethal endotoxemia in mice. J Surg Res. 1993 Apr;54(4):316–321. doi: 10.1006/jsre.1993.1050. [DOI] [PubMed] [Google Scholar]
  25. Morrison D. C., Ryan J. L. Endotoxins and disease mechanisms. Annu Rev Med. 1987;38:417–432. doi: 10.1146/annurev.me.38.020187.002221. [DOI] [PubMed] [Google Scholar]
  26. Ooi C. E., Weiss J., Doerfler M. E., Elsbach P. Endotoxin-neutralizing properties of the 25 kD N-terminal fragment and a newly isolated 30 kD C-terminal fragment of the 55-60 kD bactericidal/permeability-increasing protein of human neutrophils. J Exp Med. 1991 Sep 1;174(3):649–655. doi: 10.1084/jem.174.3.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Parrillo J. E., Parker M. M., Natanson C., Suffredini A. F., Danner R. L., Cunnion R. E., Ognibene F. P. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990 Aug 1;113(3):227–242. doi: 10.7326/0003-4819-113-3-227. [DOI] [PubMed] [Google Scholar]
  28. Pearson F. C., Dubczak J., Weary M., Bruszer G., Donohue G. Detection of endotoxin in the plasma of patients with gram-negative bacterial sepsis by the Limulus amoebocyte lysate assay. J Clin Microbiol. 1985 Jun;21(6):865–868. doi: 10.1128/jcm.21.6.865-868.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rogy M. A., Oldenburg H. S., Calvano S. E., Montegut W. J., Stackpole S. A., Van Zee K. J., Marra M. N., Scott R. W., Seilhammer J. J., Moldawer L. L. The role of bactericidal/permeability-increasing protein in the treatment of primate bacteremia and septic shock. J Clin Immunol. 1994 Mar;14(2):120–133. doi: 10.1007/BF01541345. [DOI] [PubMed] [Google Scholar]
  30. Shenep J. L., Mogan K. A. Kinetics of endotoxin release during antibiotic therapy for experimental gram-negative bacterial sepsis. J Infect Dis. 1984 Sep;150(3):380–388. doi: 10.1093/infdis/150.3.380. [DOI] [PubMed] [Google Scholar]
  31. Silva A. T., Appelmelk B. J., Buurman W. A., Bayston K. F., Cohen J. Monoclonal antibody to endotoxin core protects mice from Escherichia coli sepsis by a mechanism independent of tumor necrosis factor and interleukin-6. J Infect Dis. 1990 Aug;162(2):454–459. doi: 10.1093/infdis/162.2.454. [DOI] [PubMed] [Google Scholar]
  32. Silva A. T., Bayston K. F., Cohen J. Prophylactic and therapeutic effects of a monoclonal antibody to tumor necrosis factor-alpha in experimental gram-negative shock. J Infect Dis. 1990 Aug;162(2):421–427. doi: 10.1093/infdis/162.2.421. [DOI] [PubMed] [Google Scholar]
  33. Smith J. G., Magee D. M., Williams D. M., Graybill J. R. Tumor necrosis factor-alpha plays a role in host defense against Histoplasma capsulatum. J Infect Dis. 1990 Dec;162(6):1349–1353. doi: 10.1093/infdis/162.6.1349. [DOI] [PubMed] [Google Scholar]
  34. Starnes H. F., Jr, Pearce M. K., Tewari A., Yim J. H., Zou J. C., Abrams J. S. Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice. J Immunol. 1990 Dec 15;145(12):4185–4191. [PubMed] [Google Scholar]
  35. Sullivan J. S., Kilpatrick L., Costarino A. T., Jr, Lee S. C., Harris M. C. Correlation of plasma cytokine elevations with mortality rate in children with sepsis. J Pediatr. 1992 Apr;120(4 Pt 1):510–515. doi: 10.1016/s0022-3476(05)82476-x. [DOI] [PubMed] [Google Scholar]
  36. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  37. Van Zee K. J., Kohno T., Fischer E., Rock C. S., Moldawer L. L., Lowry S. F. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4845–4849. doi: 10.1073/pnas.89.11.4845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Waage A., Halstensen A., Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet. 1987 Feb 14;1(8529):355–357. doi: 10.1016/s0140-6736(87)91728-4. [DOI] [PubMed] [Google Scholar]
  39. Wada H., Tanigawa M., Wakita Y., Nakase T., Minamikawa K., Kaneko T., Ohiwa M., Kageyama S., Kobayashi T., Noguchi T. Increased plasma level of interleukin-6 in disseminated intravascular coagulation. Blood Coagul Fibrinolysis. 1993 Aug;4(4):583–590. doi: 10.1097/00001721-199308000-00009. [DOI] [PubMed] [Google Scholar]
  40. Weiss J., Beckerdite-Quagliata S., Elsbach P. Resistance of gram-negative bacteria to purified bactericidal leukocyte proteins: relation to binding and bacterial lipopolysaccharide structure. J Clin Invest. 1980 Mar;65(3):619–628. doi: 10.1172/JCI109707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Weiss J., Elsbach P., Shu C., Castillo J., Grinna L., Horwitz A., Theofan G. Human bactericidal/permeability-increasing protein and a recombinant NH2-terminal fragment cause killing of serum-resistant gram-negative bacteria in whole blood and inhibit tumor necrosis factor release induced by the bacteria. J Clin Invest. 1992 Sep;90(3):1122–1130. doi: 10.1172/JCI115930. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Weiss J., Muello K., Victor M., Elsbach P. The role of lipopolysaccharides in the action of the bactericidal/permeability-increasing neutrophil protein on the bacterial envelope. J Immunol. 1984 Jun;132(6):3109–3115. [PubMed] [Google Scholar]
  43. van der Poll T., Levi M., Hack C. E., ten Cate H., van Deventer S. J., Eerenberg A. J., de Groot E. R., Jansen J., Gallati H., Büller H. R. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med. 1994 Apr 1;179(4):1253–1259. doi: 10.1084/jem.179.4.1253. [DOI] [PMC free article] [PubMed] [Google Scholar]

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