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结局;然而，冷灌注相关的缺血/再灌注（I/R）损伤仍然是使移植后护理和随后的长期移植结局复杂化的主要问题。此外，最近的器官短缺要求扩大供体库，并且使用来自边缘供体的肝移植物可能增加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而受到关注。在过去的3年中，我们评估了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损伤有益处。我们推测，CO通过直接抑制枯否细胞活化和改善肝窦循环来调节促炎反应，从而保护肝移植物免受肝I/R损伤。我们将追求两个具体的目标，以探讨临床适用性，有效性和低剂量吸入CO的保护机制，在改善由于移植保存损伤的肝损伤。目的I：优化吸入CO输送以抑制肝I/R损伤。我们将充分探讨临床上适用的方式提供吸入CO的调节作用，以改善肝脏I/R损伤。将通过在围移植期给予CO作为短暂吸入治疗来确定输送方案的优化。为了最大限度地提高一氧化碳的疗效，我们将研究供体和/或受体接受一氧化碳治疗的效果。还将研究吸入一氧化碳的潜在不良后果。目的II：确定肝脏移植物共同介导保护的机制。我们将确定库普弗细胞作为CO抗炎功能的直接靶点。将在分离的细胞群中分析通过MAPK信号通路的CO介导的细胞保护的分子机制。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。本研究的长期目标是充分探索CO的调控机制，利用CO通路的益处改善早期移植肝功能，并将严重保存损伤相关的发病率降至最低。

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.