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Infection and Immunity, March 1999, p. 1353-1358, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Neutralization of Endotoxin In Vitro and In Vivo by a Human Lactoferrin-Derived Peptide

Gui-Hang Zhang,1,* David M. Mann,2,3 and Chao-Ming Tsai1

Division of Bacterial Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 208521; J. H. Holland Laboratory, Plasma Derivatives Department, American Red Cross, Rockville, Maryland 208552; and Department of Biochemistry and Molecular Biology and the Institute for Biochemical Sciences, George Washington University Medical Center, Washington, D.C. 200373

Received 31 July 1998/Returned for modification 28 September 1998/Accepted 11 December 1998

Endotoxin (lipopolysaccharide [LPS]) is the major pathogenic factor of gram-negative septic shock, and endotoxin-induced death is associated with the host overproduction of tumor necrosis factor alpha (TNF-alpha ). In the search for new antiendotoxin molecules, we studied the endotoxin-neutralizing capacity of a human lactoferrin-derived 33-mer synthetic peptide (GRRRRSVQWCAVSQPEATKCFQWQRNMRKVRGP; designated LF-33) representing the minimal sequence for lactoferrin binding to glycosaminoglycans. LF-33 inhibited the coagulation of the Limulus amebocyte lysate and the secretion of TNF-alpha by RAW 264.7 cells induced by lipid A and four different endotoxins with a potency comparable to that of polymyxin B. The first six residues at the N terminus of LF-33 were critical for its antiendotoxin activity. The endotoxin-neutralizing capacity of LF-33 and polymyxin B was attenuated by human serum. Coinjection of Escherichia coli LPS (125 ng) with LF-33 (2.5 µg) dramatically reduced the lethality of LPS in the galactosamine-sensitized mouse model. Significant protection of the mice against the lethal LPS challenge was also observed when LF-33 (100 µg) was given intravenously after intraperitoneal injection of LPS. Protection was correlated with a reduction in TNF-alpha levels in the mouse serum. These results demonstrate the endotoxin-neutralizing capability of LF-33 in vitro and in vivo and its potential use for the treatment of endotoxin-induced septic shock.

* Corresponding author. Mailing address: Plasma Derivatives Department, J. H. Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855. Phone: (301) 738-0545. Fax: (301) 738-0794. E-mail: zhanggu{at}usa.redcross.org.

Infection and Immunity, March 1999, p. 1353-1358, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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