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Infection and Immunity, November 1998, p. 5372-5378, Vol. 66, No. 11
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Mechanisms Involved in the Pathogenesis of Sepsis Are Not Necessarily Reflected by In Vitro Cell Activation Studies

Claudia R. Amura,1,dagger R. Silverstein,2 and D. C. Morrison1,3,*

Department of Microbiology, Molecular Genetics and Immunology,1 Department of Biochemistry and Molecular Biology,2 and The Kansas Cancer Institute,3 The University of Kansas Medical Center, Kansas City, Kansas 66160

Received 30 December 1997/Returned for modification 10 March 1998/Accepted 20 August 1998

It is thought that lipopolysaccharide (LPS) from gram-negative bacteria contributes significantly to the pathogenesis of septic shock. In vitro studies to address the mechanisms involved in this process have often investigated human monocytes or mouse macrophages, since these cells produce many of the mediators found in septic patients. Targeting of these mediators, especially tumor necrosis factor alpha (TNF-alpha ), has been pursued as a means of reducing mortality in sepsis. Two experimental approaches were designed to test the assumption that in vitro studies with macrophages accurately predict in vivo mechanisms of LPS pathogenesis. In the first approach, advantage was taken of the fact that on consecutive days after injection of thioglycolate into mice, increased numbers of macrophages could be harvested from the peritoneum. These cells manifested markedly enhanced levels of in vitro TNF-alpha , interleukin 6 (IL-6), and nitric oxide production in response to LPS. In D-galactosamine-sensitized mice, however, thioglycolate treatment significantly decreased mortality due to LPS, as well as levels of circulating TNF-alpha and IL-6. Anti-TNF-alpha treatment confirmed this cytokine's role in the observed lethality. In a second experimental approach, we compared the mouse macrophage-stimulating potencies of different LPS preparations with their lethalities to mice. In these studies, the in vitro macrophage-stimulating profiles presented by rough-LPS and smooth-LPS preparations were the reverse of their relative lethal potencies in vivo. In conclusion, peritoneal macrophages appear not to be the major cells responsible for the overall host response during endotoxic shock. These findings underscore the importance of verifying the correlation of in vivo systems with in vitro systems when attributing specific functions to a cell type.

* Corresponding author. Mailing address: Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, 3901 Rainbow Blvd., 1000 Wahl Hall East, Kansas City, KS 66160. Phone: (913) 588-1380. Fax: (913) 588-1388. E-mail: dmorriso{at}kumc.edu.

dagger Present address: Immunology and Respiratory Medicine, National Jewish Center, Denver, CO 80206.

Infection and Immunity, November 1998, p. 5372-5378, Vol. 66, No. 11
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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