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主要问题。此外，最近的器官短缺要求扩大供体库，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，近年来在细胞和生物过程中作为一种调节分子受到了人们的广泛关注。在过去的三年中，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对移植所致的肝I/R损伤具有保护作用。我们推测，CO通过直接抑制Kupffer细胞活化和改善正弦循环来调节促炎反应，从而保护移植肝免受肝脏I/R损伤。我们将追求两个特定的目标，以探索小剂量吸入CO在改善移植保存损伤所致肝损伤方面的临床适用性、有效性和保护机制。目的I：优化吸入CO对肝脏I/R损伤的抑制作用。我们将充分探讨临床适用的吸入CO对改善肝脏I/R损伤的调节作用。通过在移植围术期给予一氧化碳作为一种短暂的吸入治疗，将建立最佳的给药方案。为了最大限度地提高CO的疗效，我们将研究供体和/或受体接受CO治疗后的效果。还将调查吸入一氧化碳的潜在不良后果。目的II：探讨CO介导的肝移植保护机制。我们将确定库普弗细胞为CO抗炎作用的直接靶点。将在分离的细胞群体中分析通过MAPK信号通路的CO介导的抗炎保护的分子机制。我们将通过抑制星状细胞激活和内皮素(ET)系统来确定CO介导的SEC保护和肝窦循环的机制。我们在这项建议中的长期目标是通过充分探索CO的调节机制，利用CO途径的益处来改善早期肝移植功能，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.