Protective Role of Carbon Monoxide in Hepatic I/R Injury

描述（由申请人提供）：免疫抑制药物、手术技术和术后护理的进步显著改善了肝移植的预后；然而，冷保存相关的缺血/再灌注（I/R）损伤仍然是影响移植后护理和随后的长期移植结果的主要问题。此外，最近器官短缺需要扩大供体池，而使用边缘供体的肝移植可能会增加I/R损伤。一氧化碳（CO）是血红素的内源性副产物，近年来作为细胞和生物过程的调节分子受到了广泛的关注。在过去的3年里，我们已经评估了CO的细胞保护功能，并获得了令人鼓舞的结果，表明外源性吸入CO对移植诱导的肝I/R损伤有好处。我们假设CO通过直接抑制Kupffer细胞活化和改善窦状循环来调节促炎反应，从而保护肝移植物免受肝I/R损伤。我们将有两个具体的目的来探讨低剂量吸入一氧化碳在改善移植保存性损伤肝损伤中的临床适用性、疗效和保护机制。目的：优化吸入co对肝脏i / r损伤的抑制作用。我们将以临床适用的方式，充分探索吸入一氧化碳对改善肝I/R损伤的调节作用。通过在移植期给予CO作为短暂的吸入治疗，将建立优化的给药方案。为了最大限度地提高CO的疗效，我们将研究用CO治疗供体和/或受体所获得的效果。CO吸入的潜在不良后果也将被调查。目的ii：确定肝移植共介导保护的机制。我们将确定Kupffer细胞作为CO抗炎功能的直接靶点。CO通过MAPK信号通路介导的抗炎保护的分子机制将在分离细胞群中进行分析。我们将通过抑制星状细胞活化和内皮素（ET）系统来确定co介导的SEC保护和肝窦循环的机制。我们的长期目标是通过充分探索CO的调控机制，利用CO通路的益处来改善早期肝移植功能，并最大限度地减少严重保存性损伤相关的发病率。

DESCRIPTION (provided by applicant): Advancements in immunosuppressive drugs, surgical techniques, and postoperative care have significantly improved outcomes of liver transplantation; however, cold preservation-associated ischemia/reperfusion (I/R) injury remains a major problem complicating posttransplant care and subsequent long-term transplant outcomes. Further, the recent organ shortage demands to expand the donor pool, and the use of liver grafts from marginal donors possibly augments I/R injury. Carbon monoxide (CO), an endogenous byproduct of heme, has lately received notable attention as a regulatory molecule in cellular and biological processes. During the last 3 years, we have evaluated the cytoprotective function of CO and obtained encouraging results showing that exogenous inhaled CO provides benefits against transplant-induced hepatic I/R injury. We hypothesize that CO protects liver grafts from hepatic I/R injury via the regulation of proinflammatory responses by directly inhibiting Kupffer cell activation and by improving sinusoidal circulation. We will pursue two specific aims to explore the clinical applicability, efficacy, and mechanisms of protection of low dose inhaled CO in ameliorating liver damage due to transplant preservation injury. AIM I: TO OPTIMIZE INHALED CO DELIVERY TO INHIBIT LIVER I/R INJURY. We will fully explore the regulatory effects of inhaled CO delivered in a clinically applicable manner to ameliorate hepatic I/R injury. Optimization of the delivery protocol will be established by administering CO as a brief inhalation therapy during the peritransplant period. To maximize CO efficacy, we will study effects obtained with donor and/or recipient treatment with CO. The potential adverse consequences of CO inhalation will also be investigated. AIM II: TO IDENTIFY THE MECHANISMS OF CO-MEDIATED PROTECTION OF LIVER GRAFTS. We will determine Kupffer cells as CO's direct target for antiproinflammatory function. Molecular mechanisms of CO- mediated antiinflammatory protection via the MAPK signaling pathways will be analyzed in isolated cell population. We will determine the mechanism of CO-mediated SEC protection and hepatic sinusoidal circulation via the inhibition of stellate cell activation and endothelin (ET) system. Our long-term goal in this proposal is to harness the benefit of CO pathway to improve early liver graft function and minimize the morbidity associated with severe preservation injury by fully exploring the regulatory mechanisms of CO.