Mechanism of hemoglobin-induced protection against endotoxemia in rats: a ferritin independent pathway. Otterbein, Leo, Beek Yoke Chin, Sherrie L. Otterbein, Valerie C. Lowe, Henry E. Fessler, and Augustine M. K. Choi. Division of Pulmonary & Critical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and Scios-Nova Pharmaceutical Inc., Baltimore, Maryland 21224
APStracts 3:0206L, 1996.
Hemoglobin (Hb) induces heme oxygenase-1 (HO-1), which catalyzes the breakdown of heme to bilirubin, and ferritin. Rats pretreated with Hb have been shown to survive lethal doses of lipopolysaccharide (LPS) (AJRCMB 13:595-601, 1995). The physiologic basis of this increased survival and the mechanism(s) involved in the protection against LPS by Hb are unknown. Here we investigated i) the effects of Hb on the hemodynamic and biochemical parameters of LPS-induced tissue injury and ii) the mechanism(s) by which Hb conferred protection against shock and tissue injury. Hb-treated rats maintained normal mean arterial blood pressure while control rats experienced cardiovascular collapse after a lethal dose of LPS. Hepatic and renal functions, peripheral white blood cell, serum lactate dehydrogenase and phosphate also remained normal after LPS in Hb-treated rats. Hb also attenuated LPS-induced neutrophil alveolitis and tumor necrosis factor-[alpha] levels. Pretreatment with desferoxamine, which like ferritin can bind iron, and with exogenous apoferritin both failed to protect against LPS. In contrast, treatment with Hb plus desferoxamine, which induced HO-1 but not ferritin, did protect against LPS. Treatment with iron dextran, which induced ferritin but not HO-1, did not protect against LPS. We conclude that Hb pretreatment reduces the inflammatory and physiologic consequences of LPS, and that the Hb-induced protection against LPS is dependent upon HO-1 and not ferritin induction. 

Received 18 July 1996; accepted in final form 5 September 1996.
APS Manuscript Number L228-6.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996