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(Circulation. 2001;104:914.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Immunopathogenesis of Atherosclerosis

Endotoxin Accelerates Atherosclerosis in Rabbits on Hypercholesterolemic Diet

Hans-Anton Lehr, MD, PhD; Tolga Atilla Sagban; Christian Ihling, MD, PhD; Ulrich Zähringer, PhD; Klaus-Dieter Hungerer, PhD; Matthias Blumrich, PhD; Kurt Reifenberg, PhD; Sucharit Bhakdi, MD, PhD

From the Institute of Pathology (H.-A.L., T.A.S.), Central Laboratory Animal Facility (K.R.), and Institute of Medical Microbiology and Hygiene (S.B.), University of Mainz; the Department of Pathology, University of Freiburg (C.I.); Forschungszentrum Borstel, Borstel (U.Z.); and Hoechst Marion Roussel, Marburg (K.-D.H., M.B.), Germany.

Correspondence to Sucharit Bhakdi, MD, PhD, Institute of Medical Microbiology and Hygiene, Augustusplatz, D-55101 Mainz, Germany. E-mail sbhakdi{at}mail.uni-mainz.de

Background—— On the basis of our concept that atherosclerosis has an immunopathological background, we tested whether activation of the innate immune system influences its progression.

Methods and Results—— Hypercholesterolemic (0.5% wt/wt diet) rabbits received either repeated intravenous injections of endotoxin (Escherichia coli lipopolysaccharide 1.25 to 2.5 µg, once per week) or a self-limiting cutaneous Staphylococcus aureus infection with or without a quinolone antibiotic. Measured laboratory parameters, including LDL and HDL cholesterols, were similar in the different groups of hypercholesterolemic animals. All endotoxin-treated animals developed transient episodes of fever after endotoxin administration. The extent of atherosclerosis was evaluated by computer-assisted morphometry in the aortas en face (Sudan IV) and by histology at 8 weeks after start of the experiments. Endotoxin-treated animals exhibited significantly accelerated atherosclerosis compared with control animals (141±38 versus 45±16 mm³ total lesion volume, n=7 to 9 rabbits each, P<0.001).

Conclusions—— Nonspecific stimulation of the innate immune system accelerates cholesterol-induced atherosclerosis. These data support the concept that atherosclerosis has an immunopathological component and render it improbable that a single infectious agent should assume particular importance in its initiation or progression.

Key Words: imaging • immunology • atherosclerosis • endotoxin

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