Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
PLoS One. 2013 May 7;8(5):e63606. doi: 10.1371/journal.pone.0063606. Print 2013.
Hemorrhagic shock and resuscitation induces pulmonary inflammation that leads to acute lung injury. Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects. This study aimed to examine the effects of intravenous biliverdin administration on lung injury induced by hemorrhagic shock and resuscitation in rats. Biliverdin or vehicle was administered to the rats 1 h before sham or hemorrhagic shock-inducing surgery. The sham-operated rats underwent all surgical procedures except bleeding. To induce hemorrhagic shock, rats were bled to achieve a mean arterial pressure of 30 mmHg that was maintained for 60 min, followed by resuscitation with shed blood. Histopathological changes in the lungs were evaluated by histopathological scoring analysis. Inflammatory gene expression was determined by Northern blot analysis, and oxidative DNA damage was assessed by measuring 8-hydroxy-2' deoxyguanosine levels in the lungs. Hemorrhagic shock and resuscitation resulted in prominent histopathological damage, including congestion, edema, cellular infiltration, and hemorrhage. Biliverdin administration prior to hemorrhagic shock and resuscitation significantly ameliorated these lung injuries as judged by histopathological improvement. After hemorrhagic shock and resuscitation, inflammatory gene expression of tumor necrosis factor-α and inducible nitric oxide synthase were increased by 18- and 8-fold, respectively. Inflammatory gene expression significantly decreased when biliverdin was administered prior to hemorrhagic shock and resuscitation. Moreover, after hemorrhagic shock and resuscitation, lung 8-hydroxy-2' deoxyguanosine levels in mitochondrial DNA expressed in the pulmonary interstitium increased by 1.5-fold. Biliverdin administration prior to hemorrhagic shock and resuscitation decreased mitochondrial 8-hydroxy-2' deoxyguanosine levels to almost the same level as that in the control animals. We also confirmed that biliverdin administration after hemorrhagic shock and resuscitation had protective effects on lung injury. Our findings suggest that biliverdin has a protective role, at least in part, against hemorrhagic shock and resuscitation-induced lung injury through anti-inflammatory and anti-oxidant mechanisms.
失血性休克和复苏可引起肺部炎症，进而导致急性肺损伤。胆红素是血红素分解代谢的产物，已被证明具有强大的细胞保护、抗炎和抗氧化作用。本研究旨在探讨静脉内胆红素给药对失血性休克和复苏诱导的大鼠肺损伤的影响。在假手术或失血性休克诱导手术前 1 小时，给大鼠给予胆红素或载体。假手术组大鼠接受所有手术程序，但不出血。为了诱导失血性休克，将大鼠放血至平均动脉压 30mmHg，维持 60 分钟，然后用失血进行复苏。通过组织病理学评分分析评估肺组织学变化。通过 Northern blot 分析确定炎性基因表达，通过测量肺 8-羟基-2'-脱氧鸟苷水平评估氧化 DNA 损伤。失血性休克和复苏导致明显的组织病理学损伤，包括充血、水肿、细胞浸润和出血。在失血性休克和复苏之前给予胆红素给药可显著改善这些肺损伤，如组织病理学改善所示。失血性休克和复苏后，肿瘤坏死因子-α和诱导型一氧化氮合酶的炎性基因表达分别增加了 18 倍和 8 倍。在失血性休克和复苏之前给予胆红素给药可显著降低炎性基因表达。此外，在失血性休克和复苏后，肺间质中表达的线粒体 DNA 的肺 8-羟基-2'-脱氧鸟苷水平增加了 1.5 倍。在失血性休克和复苏之前给予胆红素给药可将线粒体 8-羟基-2'-脱氧鸟苷水平降低至与对照动物几乎相同的水平。我们还证实，失血性休克和复苏后给予胆红素给药对肺损伤具有保护作用。我们的研究结果表明，胆红素至少部分通过抗炎和抗氧化机制发挥对失血性休克和复苏诱导的肺损伤的保护作用。
