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Infect Immun, April 1998, p. 1400-1407, Vol. 66, No. 4
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Endotoxin-Neutralizing Protein Protects against Endotoxin-Induced Endothelial Barrier Dysfunction

Douglas D. Bannerman,1 Michael J. Fitzpatrick,1 Dell Y. Anderson,2 Apurba K. Bhattacharjee,3 Thomas J. Novitsky,4 Jeffrey D. Hasday,2 Alan S. Cross,2 and Simeon E. Goldblum2,*

Departments of Pathology1 and Medicine,2 VA Maryland Health Care System, University of Maryland School of Medicine, Baltimore, Maryland 21201; Walter Reed Army Institute of Research, Washington, D.C. 203073; and Associates of Cape Cod, Falmouth, Massachusetts 025404

Received 7 August 1997/Returned for modification 6 October 1997/Accepted 8 January 1998

Bacterial lipopolysaccharide induces tyrosine phosphorylation of paxillin, actin reorganization, and opening of the transendothelial paracellular pathway through which macromoles flux. In this study, lipid A was shown to be the bioactive portion of the lipopolysaccharide molecule responsible for changes in endothelial barrier function. We then studied whether endotoxin-neutralizing protein, a recombinant peptide that is derived from Limulus antilipopolysaccharide factor and targets lipid A, could block the effects of lipopolysaccharide on protein tyrosine phosphorylation, actin organization, and movement of 14C-bovine serum albumin across bovine pulmonary artery endothelial cell monolayers. In the presence of serum, a 6-h exposure to lipopolysaccharide (10 ng/ml) increased transendothelial 14C-albumin flux compared to the simultaneous media control. Coadministration of endotoxin-neutralizing protein (>= 10 ng/ml) with lipopolysaccharide (10 ng/ml) protected against lipopolysaccharide-induced barrier dysfunction. This protection was dose dependent, conferring total protection at endotoxin-neutralizing protein/lipopolysaccharide ratios of >= 10:1. Similarly, endotoxin-neutralizing protein was capable of blocking the lipopolysaccharide-induced endothelial cell responses that are prerequisite to barrier dysfunction, including tyrosine phosphorylation of paxillin and actin depolymerization. Finally, endotoxin-neutralizing protein cross-protected against lipopolysaccharide derived from diverse gram-negative bacteria. Thus, endotoxin-neutralizing protein offers a novel therapeutic intervention for the vascular endothelial dysfunction of gram-negative sepsis and its attendant endotoxemia.

* Corresponding author. Mailing address: Medical Service (111) Rm5D-139, Department of Veterans Affairs Medical Center, 10 North Greene St., Baltimore, MD 21201. Phone: (410) 605-7182. Fax: (410) 605-7914.




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