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Sublethal Endotoxin Administration Evokes Super-Resistance to Systemic Hypoxia in Rats

Hiki, Naoki MD, PhD; Mimura, Yoshikazu MD, PhD; Hatao, Fumihiko MD; Kojima, Junichi MD, PhD; Ogawa, Toshihisa MD, PhD; Tsuji, Eiichi MD; Kaminishi, Michio MD, PhD

The Journal of Trauma: Injury, Infection, and Critical Care: March 2003 - Volume 54 - Issue 3 - p 584-589
doi: 10.1097/01.TA.0000060180.29719.57

Backgroun  Systemic hypoxia following surgical injury modulates cytokine and catecholamine responses. Endotoxin tolerance develops after pretreatment of animals with sublethal endotoxin doses and is characterized by a reduced inflammatory cytokine response to subsequent endotoxin challenges. The administration of endotoxin also attenuates ischemic injury of rat myocardial tissue following hypoxia, a phenomenon described as cross-tolerance. The objectives of this study were: 1) to determine whether endotoxin evokes a cross-tolerance to systemic hypoxia in rats; and 2) to estimate circulatory and pulmonary performance in rats with systemic hypoxia after endotoxin pretreatment.

Methods  Seventy-two hours before the experiment, Wistar rats were given an intraperitoneal injection of endotoxin at a dose of 10 μg/kg. Polyethylene catheters were inserted into the femoral vein for infusion, and into the femoral artery for blood sampling and blood pressure monitoring. Systemic hypoxia was achieved by continuous inhalation of a modified gas mixture (9% oxygen+ 91% N2) for 4 hours. Plasma TNF-α and IL-6 were measured by ELISA, and norepinephrine (NE) by HPLC.

Results  The hypoxic rats that were pretreated with saline showed a significant decrease in mean arterial blood and base excess, as compared with the normoxic rats. Endotoxin pretreatment prevented the drop in mean arterial pressure during hypoxia and reduced the decrease in base excess. Hypoxic conditions markedly stimulated TNF-α and IL-6 release and increased NE levels, compared to the normoxic rats. Pretreatment with endotoxin suppressed the hypoxia-induced cytokine production as well as attenuating the increase in NE levels

Conclusions  In this rat hypoxia model, endotoxin pretreatment ameliorated the hypoxia-induced inflammatory response as well as suppressing the effects on arterial oxygenation, anaerobic metabolism and NE stimulation.

From the Department of Gastrointestinal Surgery, University of Tokyo, Graduate School of Medicine, Tokyo, Japan.

Submitted for publication November 29, 2001.

Accepted for publication July 8, 2002.

Address for reprints: Naoki Hiki, MD, PhD, 7-3-1 Hongo, Bunkyou-Ku, Tokyo 113-8655; email:

© 2003 Lippincott Williams & Wilkins, Inc.