Otterbein L, Chin B Y, Otterbein S L, Lowe V C, Fessler H E, Choi A M
Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Am J Physiol. 1997 Feb;272(2 Pt 1):L268-75. doi: 10.1152/ajplung.1997.272.2.L268.
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; see L. Otterbein, S. L. Sylvester, and A. M. Choi. Am. J. Respir. Cell Mol. Biol. 13: 595-601, 1995). The physiological basis of this increased survival and the mechanism(s) involved in the protection against LPS by Hb are unknown. Here we investigated 1) the effects of Hb on the hemodynamic and biochemical parameters of LPS-induced tissue injury and 2) the mechanism(s) by which Hb conferred protection against shock and tissue injury. Hb-treated rats maintained normal mean arterial blood pressure, whereas control rats experienced cardiovascular collapse after a lethal dose of LPS. Hepatic and renal functions, peripheral white blood cells, 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 both desferoxamine, which, like ferritin, can bind iron, and with exogenous apoferritin 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 physiological consequences of LPS and that the Hb-induced protection against LPS is dependent on HO-1 and not ferritin induction.
血红蛋白（Hb）可诱导血红素加氧酶-1（HO-1），后者催化血红素分解为胆红素和铁蛋白。已证明，预先用Hb处理的大鼠能够在致死剂量的脂多糖（LPS）作用下存活（见L. Otterbein、S. L. Sylvester和A. M. Choi。《美国呼吸细胞与分子生物学杂志》13: 595 - 601, 1995）。这种存活率提高的生理基础以及Hb对抗LPS的保护机制尚不清楚。在此，我们研究了1）Hb对LPS诱导的组织损伤的血流动力学和生化参数的影响，以及2）Hb赋予抗休克和组织损伤保护作用的机制。经Hb处理的大鼠维持正常的平均动脉血压，而对照大鼠在接受致死剂量的LPS后出现心血管衰竭。经Hb处理的大鼠在接受LPS后，肝肾功能、外周白细胞、血清乳酸脱氢酶和磷酸盐也保持正常。Hb还减轻了LPS诱导的中性粒细胞肺泡炎和肿瘤坏死因子-α水平。与铁蛋白一样能结合铁的去铁胺以及外源性脱铁铁蛋白的预处理均未能提供抗LPS的保护作用。相反，用Hb加去铁胺处理可诱导HO-1但不诱导铁蛋白，确实能提供抗LPS的保护作用。用右旋糖酐铁处理可诱导铁蛋白但不诱导HO-1，不能提供抗LPS的保护作用。我们得出结论，Hb预处理可减轻LPS的炎症和生理后果，且Hb诱导的抗LPS保护作用依赖于HO-1而非铁蛋白的诱导。
