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Free access | 10.1172/JCI106020

The role of endotoxin during typhoid fever and tularemia in man: IV. The integrity of the endotoxin tolerance mechanisms during infection

Sheldon E. Greisman, Richard B. Hornick, Henry N. Wagner Jr., William E. Woodward, and Theodore E. Woodward

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland 21201

Find articles by Greisman, S. in: PubMed | Google Scholar

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland 21201

Find articles by Hornick, R. in: PubMed | Google Scholar

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland 21201

Find articles by Wagner, H. in: PubMed | Google Scholar

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland 21201

Find articles by Woodward, W. in: PubMed | Google Scholar

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland 21201

Find articles by Woodward, T. in: PubMed | Google Scholar

Published April 1, 1969 - More info

Published in Volume 48, Issue 4 on April 1, 1969
J Clin Invest. 1969;48(4):613–629. https://doi.org/10.1172/JCI106020.
© 1969 The American Society for Clinical Investigation
Published April 1, 1969 - Version history
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Abstract

Volunteers infected with Salmonella typhosa develop a remarkable hyperreactivity to the pyrogenic and subjective toxic activities of homologous (S. typhos) and heterologous (Pseudomonas) endotoxins. The present studies quantitate this augmented reactivity and demonstrate by three differing approaches that significant tolerance to these endotoxins can be readily induced within the framework of the hyperreactive state. Thus, (a) tolerance induced before illness by repeated daily intravenous injections of the endotoxins remained demonstrable during overt illness, (b) daily intravenous injections of the endotoxins begun during overt illness evoked progressively increasing tolerance, and (c) continuous intravenous infusions of S. typhosa endotoxin during illness rapidly induced a pyrogenic refractory state. Despite unequivocal activation of the endotoxin tolerance mechanisms by any of the above methods, the febrile and toxic course of typhoid fever proceeded unabated. Similarly, in other volunteers with Pasteurella tularensis infection, continuous intravenous infusions of S. typhosa endotoxin evoked initial hyperreactive febrile and subjective toxic responses followed by rapid appearance of a pyrogenic refractory state without modification of the underlying clinical illness. These observations suggest that circulating endotoxin plays no major role in pathogenesis of the sustained fever and toxemia during typhoid fever and tularemia in man.

The mechanisms responsible for the systemic hyperreactivity to endotoxin during typhoid fever and tularemia were further investigated. Low grade endotoxemia, nonspecific effects of tissue injury, impaired ability of the reticuloendothelial system to clear circulating endotoxin, and production of cytophilic antibodies capable of sensitizing leukocytes to endotoxin did not appear responsible. Inflammatory reactions to intradermal S. typhosa endotoxin increased significantly during typhoid fever. However, since no such dermal hyperreactivity developed to Pseudomonas endotoxin during typhoid fever nor to S. typhosa endotoxin during tularemia, the systemic hyperreactivity to bacterial endotoxins during typhoid fever and tularemia could not presently be ascribed to enhanced levels of acquired hypersensitivity.

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