Balla J, Nath K A, Balla G, Juckett M B, Jacob H S, Vercellotti G M
Department of Medicine, University of Minnesota, Minneapolis 55455.
Am J Physiol. 1995 Feb;268(2 Pt 1):L321-7. doi: 10.1152/ajplung.1995.268.2.L321.
Iron-derived reactive oxygen species play an important role in the pathogenesis of various vascular disorders including vasculitis, atherosclerosis, and capillary leak syndromes such as the adult respiratory distress syndrome (ARDS). We have suggested that acute incorporation of the heme moiety of hemoglobin released from red blood cells into endothelium could provide catalytically active iron to the vasculature. Adaptation to chronic heme stress involves the induction of heme oxygenase and ferritin; the latter provides cytoprotection against free radicals in vitro. The present studies examine the bioavailability of heme, derived from hemoglobin, to induce heme oxygenase and ferritin in rat lungs in vivo. Intravenous injection of methemoglobin, but not oxyhemoglobin, increases total lung heme oxygenase mRNA approximately fivefold after 16 h. Accompanying this mRNA induction, expression of total lung heme oxygenase enzyme activity is also markedly enhanced. In situ hybridization for heme oxygenase reveals mRNA accumulation in the lung microvascular endothelium, implying incorporation of heme into endothelial cells. Similarly, methemoglobin significantly increases the ferritin protein content of rat lungs and in parallel, ferritin light-chain mRNA increases approximately 1.6-fold, whereas heavy-chain mRNA is upregulated by approximately 1.9-fold. Immunoreactive ferritin is present in lung microvascular endothelium after methemoglobin treatment, suggesting incorporation of heme iron into pulmonary vasculature. Subcutaneous injection of Sn-protoporphyrin IX, a competitive inhibitor of heme oxygenase, does not affect methemoglobin-induced ferritin synthesis in lungs. We speculate that methemoglobin, which might be generated by activated leukocytes in ARDS associated with disseminated interavascular coagulation, can provide heme iron to lung microvascular endothelium to induce heme oxygenase and ferritin.
铁衍生的活性氧在多种血管疾病的发病机制中起重要作用，这些疾病包括血管炎、动脉粥样硬化以及诸如成人呼吸窘迫综合征（ARDS）等毛细血管渗漏综合征。我们曾提出，红细胞释放的血红蛋白血红素部分急性掺入内皮细胞可为血管系统提供具有催化活性的铁。对慢性血红素应激的适应涉及血红素加氧酶和铁蛋白的诱导；后者在体外提供针对自由基的细胞保护作用。本研究检测了源自血红蛋白的血红素在大鼠体内诱导肺组织中血红素加氧酶和铁蛋白的生物利用度。静脉注射高铁血红蛋白而非氧合血红蛋白，16小时后可使肺组织中血红素加氧酶的总mRNA增加约五倍。伴随这种mRNA的诱导，肺组织中血红素加氧酶的总酶活性表达也显著增强。血红素加氧酶的原位杂交显示mRNA在肺微血管内皮细胞中积累，这意味着血红素掺入了内皮细胞。同样，高铁血红蛋白显著增加大鼠肺组织中铁蛋白的蛋白质含量，同时，铁蛋白轻链mRNA增加约1.6倍，而重链mRNA上调约1.9倍。高铁血红蛋白处理后，免疫反应性铁蛋白存在于肺微血管内皮细胞中，提示血红素铁掺入了肺血管系统。皮下注射血红素加氧酶的竞争性抑制剂锡原卟啉IX，并不影响高铁血红蛋白诱导的肺组织中铁蛋白合成。我们推测，在与弥散性血管内凝血相关的ARDS中，由活化白细胞产生的高铁血红蛋白可向肺微血管内皮细胞提供血红素铁，从而诱导血红素加氧酶和铁蛋白。
