Protective Role of Carbon Monoxide in Hepatic I/R Injury

描述（申请人提供）：免疫抑制药物、手术技术和术后护理的进步显着改善了肝移植的效果；然而，冷保存相关的缺血/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果复杂化的一个主要问题。此外，最近的器官短缺需要扩大供体库，而使用边缘供体的肝移植可能会加剧缺血再灌注损伤。一氧化碳 (CO) 是血红素的内源性副产物，最近作为细胞和生物过程中的调节分子受到了广泛关注。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 可对抗移植引起的肝 I/R 损伤。我们假设 CO 通过直接抑制库普弗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目标，探索低剂量吸入CO在改善移植保存损伤引起的肝损伤中的临床适用性、功效和保护机制。目标 I：优化吸入 CO 输送以抑制肝 I/R 损伤。我们将充分探索以临床适用的方式吸入CO对改善肝缺血再灌注损伤的调节作用。将通过在围移植期间给予 CO 作为短暂吸入疗法来建立优化的递送方案。为了最大限度地提高 CO 功效，我们将研究用 CO 治疗供体和/或受体所获得的效果。还将研究吸入 CO 的潜在不良后果。目标 II：确定肝移植物的协同保护机制。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 CO 介导的通过 MAPK 信号通路介导的抗炎保护的分子机制。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。我们在该提案中的长期目标是通过充分探索CO的调节机制，利用CO途径的优势来改善早期肝移植功能，并最大限度地减少与严重保存损伤相关的发病率。

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.