HEMOGLOBIN PROVIDES PROTECTION AGAINST LETHAL ENDOTOXEMIA IN RATS - THE ROLE OF HEME OXYGENASE-1

Heme oxygenase (HO) catalyzes the rate-limiting step in the degradatio n of heme to bilirubin, HO-1 is highly induced by heme, its major subs trate, and nonheme products, including metal ions and hormones. Intere st in HO-1 has been stimulated recently by observations that HO-1 is a lso highly induced in response to oxidative stress in vitro, The physi ologic 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 th e lung responds to LPS by expressing high levels of HO-1 mRNA and enzy me activity. We hypothesize that this HO-1 induction could play a crit ical 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 letha l endotoxemia (100% survival). Tin protoporphyrin, a competitive inhib itor of HO, blocked this protective effect of hemoglobin and rendered the rats more susceptible to a lethal dose of LPS, Taken together, the se data strongly implicate HO-1 in playing an important role in the de fense against endotoxic shock, with potential therapeutic implications .