AJP - Gastrointestinal and Liver Physiology, Vol 271, Issue 4 539-G548, Copyright © 1996 by American Physiological Society

ARTICLES

Inhibition of nitric oxide synthase gene expression in vivo and in vitro by repeated doses of endotoxin

C. C. Chang, C. C. McCormick, A. W. Lin, R. R. Dietert and Y. J. Sung
Division of Nutritional Sciences, Cornell University, Ithoca, New York 14853, USA.

We have examined the effects of repeated endotoxin administration in vivo and in vitro on the induction of nitric oxide synthase (NOS). In vivo, hepatic NOS activity and mRNA were increased markedly by the administration of Escherichia coli lipopolysaccharide (LPS). The change in hepatic NOS activity coincided with a marked accumulation of hepatic citrulline. Both enzyme activity and citrulline concentration returned to normal by 12 h after LPS administration. At this time, a subsequent administration of endotoxin caused no change in either NOS mRNA, NOS activity, or citrulline concentration, and thus an endotoxin-refractory state for nitric oxide (NO) synthesis was established. Normal sensitivity was reestablished by 24 h after the initial dose. In vitro studies using both a macrophage cell line (HD11) and primary macrophages indicated that LPS pretreatment caused cells in culture to become completely refractory to subsequent stimulation by LPS. Finally, we tested the hypothesis that NO may be involved in the development of the refractory state. Various inhibitors blocked the initial synthesis of NO by > 90% but failed to influence the development of the refractory state. Our study demonstrates both in vivo and in vitro that NO synthesis is completely blocked after repeated exposure to endotoxin by a mechanism that appears to be pretranslational. This model of early endotoxin tolerance may provide insight into the molecular mechanisms that regulate expression of the NOS gene.

This article has been cited by other articles:

				C. C. Teixeira, K. Mansfield, C. Hertkorn, H. Ischiropoulos, and I. M. Shapiro Phosphate-induced chondrocyte apoptosis is linked to nitric oxide generation Am J Physiol Cell Physiol, September 1, 2001; 281(3): C833 - C839. [Abstract] [Full Text] [PDF]

				H. S. Moeniralam, F. Sprangers, E. Endert, M. T. Ackermans, J. J. B. Van Lanschot, H. P. Sauerwein, and J. A. Romijn Role of nitric oxide in the regulation of glucose kinetics in response to endotoxin in dogs J Appl Physiol, July 1, 2001; 91(1): 130 - 136. [Abstract] [Full Text] [PDF]

				P. Bauer, T. Welbourne, T. Shigematsu, J. Russell, and D. N. Granger Endothelial expression of selectins during endotoxin preconditioning Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2000; 279(6): R2015 - R2021. [Abstract] [Full Text] [PDF]

				A. Stadnicki, J. Chao, I. Stadnicka, E. Van Tol, K.-F. Lin, F. Li, R. B. Sartor, and R. W. Colman Localization and secretion of tissue kallikrein in peptidoglycan-induced enterocolitis in Lewis rats Am J Physiol Gastrointest Liver Physiol, October 1, 1998; 275(4): G854 - G861. [Abstract] [Full Text] [PDF]