Kubulus Darius, Mathes Alexander, Pradarutti Sascha, Raddatz Alexander, Heiser Jochen, Pavlidis Daphne, Wolf Beate, Bauer Inge, Rensing Hauke
Department of Anesthesiology, Critical Care and Pain Medicine, University of the Saarland, Homburg, Germany.
Shock. 2008 May;29(5):583-90. doi: 10.1097/SHK.0b013e318157e526.
Microvascular failure is a major determinant for the development of hepatocellular dysfunction after hemorrhagic shock. Induction of heme oxygenase (HO) 1 may confer hepatocellular protection. Hemin arginate (HAR) induces HO-1 and protects against shock-induced organ failure. The mechanisms are not completely understood, but HO-1-mediated protective effects on the microcirculation and on the inflammatory response may contribute. Therefore, the aim of the present study was to investigate the influence of HAR pretreatment on liver microcirculation and cytokine response to assess the role of HO-1-mediated effects under these conditions. Male Sprague-Dawley rats (200-300 g; n=8 per group) were subjected to hemorrhage (MAP, 30-40 mmHg for 1 h) 24 h after pretreatment with vehicle (Ringer solution) or HAR (5 mg kg(-1)), followed by 2 h of resuscitation. The microcirculation and the redox state (nicotinamide adenine dinucleotide phosphate [reduced form; NADPH] autofluorescence) of the liver were assessed using intravital microscopy. Cytokine levels (TNF-alpha and IL-10) were quantified using an enzyme-linked immunosorbent assay. A profound induction of HO-1 was observed 24 h after pretreatment with HAR. Hemorrhage significantly reduced sinusoidal perfusion and increased NADPH autofluorescence and cytokine levels. Hemin arginate pretreatment significantly improved liver microcirculation, reduced NADPH autofluorescence, significantly increased IL-10, and tended to decrease TNF-alpha serum levels compared with shock vehicle. Blockade of the HO pathway with tin-mesoporphyrin-IX after HAR pretreatment abolished the observed beneficial effects, whereas the additional administration of the carbon monoxide donor dichloromethane reversed the tin-mesoporphyrin-IX-mediated changes. These results suggest that HAR pretreatment improves liver microcirculation and mediates an anti-inflammatory cytokine response after hemorrhagic shock through induction of HO-1 and in part through an increased carbon monoxide release.
微血管功能障碍是失血性休克后肝细胞功能障碍发生的主要决定因素。诱导血红素加氧酶（HO）1可能对肝细胞起到保护作用。精氨酸血红素（HAR）可诱导HO-1表达，并预防休克诱导的器官功能衰竭。其机制尚未完全明确，但HO-1介导的对微循环和炎症反应的保护作用可能发挥了作用。因此，本研究旨在探讨HAR预处理对肝脏微循环及细胞因子反应的影响，以评估在此条件下HO-1介导效应的作用。雄性Sprague-Dawley大鼠（200 - 300 g；每组n = 8）在分别用溶媒（林格液）或HAR（5 mg·kg⁻¹）预处理24小时后进行出血（平均动脉压30 - 40 mmHg，持续1小时），随后进行2小时的复苏。使用活体显微镜评估肝脏的微循环和氧化还原状态（还原型烟酰胺腺嘌呤二核苷酸磷酸[NADPH]自发荧光）。使用酶联免疫吸附测定法定量细胞因子水平（肿瘤坏死因子-α和白细胞介素-10）。在用HAR预处理24小时后观察到HO-1的显著诱导。出血显著减少了肝窦灌注，增加了NADPH自发荧光和细胞因子水平。与休克溶媒组相比，精氨酸血红素预处理显著改善了肝脏微循环，降低了NADPH自发荧光，显著增加了白细胞介素-10，并使肿瘤坏死因子-α血清水平有降低趋势。在HAR预处理后用锡中卟啉-IX阻断HO途径消除了观察到的有益效果，而额外给予一氧化碳供体二氯甲烷可逆转锡中卟啉-IX介导的变化。这些结果表明，HAR预处理可改善失血性休克后的肝脏微循环，并通过诱导HO-1以及部分通过增加一氧化碳释放介导抗炎细胞因子反应。
