Otterbein L, Sylvester S L, Choi A M
Scios-Nova Pharmaceutical Inc., Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Am J Respir Cell Mol Biol. 1995 Nov;13(5):595-601. doi: 10.1165/ajrcmb.13.5.7576696.
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.
血红素加氧酶（HO）催化血红素降解为胆红素的限速步骤。HO-1可被其主要底物血红素以及包括金属离子和激素在内的非血红素产物高度诱导。最近，由于观察到HO-1在体外对氧化应激也有高度诱导作用，人们对它的兴趣大增。然而，体内氧化损伤后诱导HO-1的生理意义却知之甚少。在脂多糖内毒素（LPS）诱导的大鼠肺损伤和脓毒症模型中，我们证明肺通过表达高水平的HO-1 mRNA和酶活性来对LPS作出反应。我们推测这种HO-1的诱导可能在肺对LPS的防御中起关键作用。用HO-1的强效诱导剂血红蛋白对大鼠进行预处理，可诱导HO-1，更重要的是能为后续的致死性内毒素血症提供完全保护（存活率100%）。HO的竞争性抑制剂锡原卟啉可阻断血红蛋白的这种保护作用，使大鼠对致死剂量的LPS更敏感。综上所述，这些数据有力地表明HO-1在对内毒素休克的防御中起重要作用，具有潜在的治疗意义。
