Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1.
Heme oxygenase (HO) catalyzes the rate-limiting step in the degradation of heme to bilirubin. HO-1 is highly induced by heme, its major substrate, and nonheme products, including metal ions and hormones. Interest in HO-1 has been stimulated recently by observations that HO-1 is also highly induced in response to oxidative stress in vitro. The physiologic significance of HO-1 induction following oxidant injury in vivo, however, is poorly understood. In a rat model of lipopolysaccharide endotoxin (LPS)-induced lung injury and sepsis, we demonstrate that the lung responds to LPS by expressing high levels of HO-1 mRNA and enzyme activity. We hypothesize that this HO-1 induction could play a critical role in the lung's defense against LPS. Pretreatment of rats with hemoglobin, a potent inducer of HO-1, resulted in HO-1 induction and more importantly provided complete protection against subsequent lethal endotoxemia (100% survival). Tin protoporphyrin, a competitive inhibitor of HO, blocked this protective effect of hemoglobin and rendered the rats more susceptible to a lethal dose of LPS. Taken together, these data strongly implicate HO-1 in playing an important role in the defense against endotoxic shock, with potential therapeutic implications.
Otterbein
L
L
Scios-Nova Pharmaceutical Inc., Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Sylvester
S L
SL
Choi
A M
AM
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000502:physiology*; D006454:Hemoglobins / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000201:enzymology*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000517:prevention & control
D004791:Enzyme Inhibitors; D006454:Hemoglobins; D008070:Lipopolysaccharides; D008665:Metalloporphyrins; D011524:Protoporphyrins; D012333:RNA, Messenger; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing)