PACAP Mediated Neural Regulation of Hepatic Inflammation in Orthotopic Liver Transplantation

 描述（由申请人提供）：由于器官取出、冷保存和手术期间的一段时间热缺血，缺血再灌注损伤（IRI）通常导致原发性移植物无功能，可能易发生晚期慢性排斥反应，并导致可用于移植的供体器官短缺。目前，没有特定的治疗方法可以预防移植受者的IRI。此外，IR诱导的组织损伤的机制以及临床相关的先天免疫应答如何促成移植物排斥反应代表了临床肝移植中最具挑战性但未充分研究的问题之一。我们已经确定了内源性PACAP神经肽在维持肝脏内稳态的作用，在非移植模型的肝脏“温暖”IRI。我们已经表明，用PACAP神经肽治疗通过以cAMP-PKA依赖性方式抑制巨噬细胞功能来改善肝脏IRI。我们正在进行的临床研究的初步数据表明，PACAP及其受体优先诱导人类IRI-resistant肝移植，相比那些患有严重的IR-损伤。在这里，我们建议分析不同的PACAP信号通路的功能，在临床相关的小鼠模型长期肝冷缺血，然后原位肝移植（奥尔特）。假设：巨噬细胞（先天免疫臂）-肝细胞（防御臂）界面处的PACAP介导的cAMP-PKA信号传导调节IRI所致OLT的促炎（致病）和细胞保护（稳态）功能。目的1：探讨PACAP神经肽在肝脏IRI天然免疫功能中的作用。假设：PACAP抑制IR应激OLT中TLR 4巨噬细胞活化并促进免疫稳态。目的2：探讨PACAP神经肽在肝缺血再灌注损伤中的保肝作用。假设：PACAP增强实质细胞自噬并促进肝细胞存活。通过在IR应激OLT的环境中识别新的PACAP介导的神经调节，该提议在先天免疫和实质细胞保护的全新背景下提出了肝脏免疫调节的进展。基于我们的初步实验数据，并得到临床观察的支持，这种探索性建议的结果可能具有深远的基础和实际影响，因为现在认为在移植部位驯服IR触发的先天性炎症对于改善短期和长期移植结果至关重要。

 DESCRIPTION (provided by applicant): Resulting from organ retrieval, cold preservation and a period of warm ischemia during the surgery, ischemia-reperfusion injury (IRI) often leads to primary graft non-function, may predispose to late chronic rejection, and contributes to the shortage of donor organs available for transplantation. At present, there is no specific treatment available to prevent IRI in transplant recipients. Moreover, mechanisms of IR-induced tissue damage, and how clinically-relevant innate immune responses contribute to graft rejection represents one of the most challenging yet understudied problems in clinical liver transplantation. We have identified the role of intrinsic PACAP neuropeptide in maintaining hepatic homeostasis in a non-transplant model of hepatic "warm" IRI. We have shown that treatment with PACAP neuropeptide ameliorated liver IRI by depressing macrophage function in cAMP-PKA dependent manner. Our pilot data from an ongoing clinical study show that PACAP and its receptors are preferentially induced in human IRI-resistant liver transplants, as compared to those suffering from severe IR-damage. Here, we propose to analyze the function of distinct PACAP signaling pathways in a clinically relevant mouse model of prolonged hepatic cold ischemia followed by orthotopic liver transplantation (OLT). Hypothesis: PACAP-mediated cAMP-PKA signaling at the macrophage (innate immune arm) - hepatocyte (defensive arm) interface regulates pro-inflammatory (pathogenic) and cytoprotective (homeostatic) functions in OLTs subjected to IRI. Aim 1: To define the role of PACAP neuropeptide in innate immune function in liver IRI. Hypothesis: PACAP inhibits TLR4 macrophage activation and promotes immune homeostasis in IR-stressed OLTs. Aim 2: To evaluate the role of PACAP neuropeptide in hepatoprotection in liver IRI. Hypothesis: PACAP enhances parenchyma cell autophagy and promotes hepatocyte survival. By identifying a novel PACAP mediated-neural regulation in the milieu of IR-stressed OLTs, this proposal puts forth the advances in hepatic immune modulation in a completely new context of innate immunity and parenchyma cytoprotection. Based on our preliminary experimental data, supported by clinical observations, findings from this exploratory proposal may have far reaching basic and practical ramifications, as taming of IR-triggered innate inflammation at the graft site is now considered critical for improving both short and long-term transplantation outcomes.