Journal of Endotoxin Research

 

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Journal of Endotoxin Research, Vol. 3, No. 6, 445-454 (1996)
DOI: 10.1177/096805199600300602

Inhibition of LPS-induced systemic and local TNF production by a synthetic anti-endotoxin peptide (SAEP-2)

M.T. Demitri

Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, Italy

M. Velucchi

Bios Ynth srl, Rapolano Terme, Siena, Italy

L. Bracci

Department of Molecular Biology, University of Siena, Siena, Italy

A. Rustici

Bios Ynth srl, Rapolano Terme, Siena, Italy

M. Porro

Bios Ynth srl, Rapolano Terme, Siena, Italy

P. Villa

Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, Italy, CNR Cellular and Molecular Pharmacology Center, Milano, Italy

P. Ghezzi

Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, Italy

Lipopolysaccharide (LPS) exerts its biological activity through the lipid A moiety. We tested the efficiency in inhibiting TNF production in sera and in tissues of mice and in the derma of rabbits challenged with LPS, of a synthetic anti-LPS peptide (SAEP-2) previously shown to specifically detoxify the lipid A region of LPS on the basis of structural similarities with the antibiotic polymyxin B (PMXB). In mice, SAEP-2 (100 µg/mouse, i.v.) injected with various schedules ('-30 to +10 min from LPS at 50 ng/mouse, i.v.) significantly inhibited serum TNF as well as liver, spleen and lung-associated TNF. In rabbits, SAEP-2 significantly inhibited TNF produced in dermal tissue and the resulting local hemorrhagic necrosis. The amount of tissue-associated TNF released by LPS challenge in the mouse was up to 6 times that present in the serum and inhibition by SAEP-2 or PMXB accounted for 75% of the total. Direct measurement of the binding kinetics by surface plasmon resonance and molecular filtration at equilibrium revealed that SAEP-2 and PMXB bind to LPS only in the presence of a significant amount of water but that they are unable to bind LPS in undiluted serum. Altogether these findings strongly suggest that inhibition of LPS-induced TNF by SAEP-2 and PMXB may occur in tissues.


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