Brunyanszki Attila, Erdelyi Katalin, Szczesny Bartosz, Olah Gabor, Salomao Reinaldo, Herndon David N, Szabo Csaba
Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Shriners Hospital for Children, Galveston, Texas, United States of America.
Mol Med. 2015 Nov;21(1):666-675. doi: 10.2119/molmed.2015.00187. Epub 2015 Aug 17.
The classical role of hemoglobin in the erythrocytes is to carry oxygen from the lungs to the tissues via the circulation. However, hemoglobin also acts as a redox regulator and as a scavenger of the gaseous mediators nitric oxide (NO) and hydrogen sulfide (HS). Here we show that upregulation of hemoglobin (α, β and δ variants of globin proteins) occurs in human peripheral blood mononuclear cells (PBMCs) in critical illness (patients with severe third-degree burn injury and patients with sepsis). The increase in intracellular hemoglobin concentration is a result of a combination of enhanced protein expression and uptake from the extra-cellular space via a CD163-dependent mechanism. Intracellular hemoglobin preferentially localizes to the mitochondria, where it interacts with complex I and, on the one hand, increases mitochondrial respiratory rate and mitochondrial membrane potential, and on the other hand, protects from HO-induced cytotoxicity and mitochondrial DNA damage. Both burn injury and sepsis were associated with increased plasma levels of HS. Incubation of mononuclear cells with HS induced hemoglobin mRNA upregulation in PBMCs . Intracellular hemoglobin upregulation conferred a protective effect against cell dysfunction elicited by HS. Hemoglobin uptake also was associated with a protection from, and induced the upregulation of, HIF-1α and Nrf2 mRNA. In conclusion, PBMCs in critical illness upregulate their intracellular hemoglobin levels by a combination of active synthesis and uptake from the extracellular medium. We propose that this process serves as a defense mechanism protecting the cell against cytotoxic concentrations of HS and other gaseous transmitters, oxidants and free radicals produced in critically ill patients.
血红蛋白在红细胞中的经典作用是通过血液循环将氧气从肺部输送到组织。然而，血红蛋白还可作为氧化还原调节剂以及气体介质一氧化氮（NO）和硫化氢（HS）的清除剂。在此我们表明，在危重病（严重三度烧伤患者和脓毒症患者）中，人类外周血单核细胞（PBMC）中血红蛋白（球蛋白蛋白的α、β和δ变体）会发生上调。细胞内血红蛋白浓度的增加是蛋白质表达增强以及通过CD163依赖性机制从细胞外空间摄取这两种因素共同作用的结果。细胞内血红蛋白优先定位于线粒体，在那里它与复合体I相互作用，一方面增加线粒体呼吸速率和线粒体膜电位，另一方面保护细胞免受HO诱导的细胞毒性和线粒体DNA损伤。烧伤和脓毒症均与血浆中HS水平升高有关。用HS孵育单核细胞可诱导PBMC中血红蛋白mRNA上调。细胞内血红蛋白上调对HS引起的细胞功能障碍具有保护作用。血红蛋白摄取还与对HIF-1α和Nrf2 mRNA的保护作用以及它们的上调有关。总之，危重病中的PBMC通过主动合成和从细胞外介质摄取相结合的方式上调其细胞内血红蛋白水平。我们认为，这一过程作为一种防御机制，可保护细胞免受危重病患者体内产生的细胞毒性浓度的HS以及其他气体递质、氧化剂和自由基的伤害。
