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Infection and Immunity, January 2002, p. 192-198, Vol. 70, No. 1
0019-9567/01/$04.00+0     DOI: 10.1128/IAI.70.1.192-198.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Comparison of Inflammation, Organ Damage, and Oxidant Stress Induced by Salmonella enterica Serovar Muenchen Flagellin and Serovar Enteritidis Lipopolysaccharide

Lucas Liaudet,^1,2,3 Kanneganti G. K. Murthy,¹ Jon G. Mabley,¹ Pál Pacher,^1, Francisco G. Soriano,^1,2, Andrew L. Salzman,¹ and Csaba Szabó^1,2*

Inotek Corporation, Beverly, Massachusetts 01915,¹ Department of Surgery, New Jersey Medical School, UMDNJ, Newark, New Jersey 01703,² Critical Care Division, Department of Internal Medicine, University Hospital, 1010 Lausanne, Switzerland³

Received 25 June 2001/ Returned for modification 11 September 2001/ Accepted 12 October 2001

Gram-negative sepsis is related to the activation of interconnected inflammatory cascades in response to bacteria and their products. Recent work showed that flagellin, the monomeric subunit of bacterial flagella, triggers innate immune responses mediated by Toll-like receptor 5. Here, we compared the effects of Salmonella enterica serovar Enteritidis lipopolysaccharide (LPS) and recombinant Salmonella enterica serovar Muenchen flagellin administered intravenously (100 µg) to mice. Flagellin and LPS both elicited a prototypical systemic inflammatory response, with increased levels of tumor necrosis factor alpha, gamma interferon, interleukin 6 and 10, and nitrate in plasma. Flagellin induced a widespread oxidative stress, evidenced by an increase in malondialdehyde and a decrease in reduced glutathione in most organs, as well as liver (increased plasma aminotransferases), but not renal, injury. Alternatively, LPS resulted in a less severe oxidative stress and triggered renal, but not liver, damage. Sequestration of polymorphonuclear neutrophils (increased myeloperoxidase activity) in the lungs was observed with both toxins, while only LPS recruited neutrophils in the gut. In additional experiments, the simultaneous administration of small doses of LPS and flagellin (10 µg) induced a synergistic enhancement of the production of proinflammatory cytokines. Our data support a novel concept implicating flagellin as a mediator of systemic inflammation, oxidant stress, and organ damage induced by gram-negative bacteria.

Editor: R. N. Moore

Permanent address: Department of Pharmacology and Pharmacotherapy, Semmelweis University Medical School, Budapest, Hungary.

Permanent address: Department of Critical Care Medicine, Hospital das Clinicas Da Universidade de Sao Paulo, Sao Paulo, Brazil.

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