CXC CHEMOKINES AND LIVER REGENERATION

炎症是宿主对损伤反应的关键组成部分， 感染，与组织修复和伤口愈合密切相关。 炎症介质，如CXC趋化因子，在 对肝脏损伤的反应。CXC趋化因子，包括上皮性 中性粒细胞激活蛋白ENA-78与巨噬细胞炎症 蛋白-2(MIP-2)是由肿瘤坏死因子-α(TNF)和 以中性粒细胞趋化和血管生成特性而闻名。他们 是肝损伤后肝脏炎症的重要组成部分。 一些CXC趋化因子在其 氨基末端，ELR序列(Glu-Leu-Arg)；它定义了 分子的生物活性，特别是中性粒细胞的趋化和 血管生成。这个家族的其他分子，包括干扰素-伽马- 干扰素-γ(MIG)诱导的诱导蛋白(IP-10)和单核细胞因子； 缺乏这一序列，因此缺乏中性粒细胞趋化活性， 有血管抑制作用，并抑制血管生成诱导的ELR含有 趋化因子。最近的研究表明，CXC趋化因子具有 促血管生成和中性粒细胞的促有丝分裂作用 趋化性。本实验室用大鼠肺叶模型进行的实验研究 肝脏缺血/再灌流表明，作为反应，肿瘤坏死因子被释放。 对肝脏缺血/再灌流的影响。这种肿瘤坏死因子然后触发肝脏ENA-78 释放，这对中性粒细胞的流入和血管紧张素转换酶的发展具有重要意义。 受伤的肝脏发炎。有趣的是，ENA-78的峰值水平 发生在再灌流24小时，也就是高峰期之后 肝中性粒细胞流入。这一观察结果，加上最近的 描述了CXC趋化因子的血管生成和有丝分裂的作用，引导我们 假设ENA-78在该模型中扮演额外角色， 可能有助于启动肝脏修复和再生。我们的 含CXC趋化因子ENA-78和ENA-78的ELR MIP-2，引起肝细胞增殖。相比之下，ELR为负值 IP-10和MIG分子不能诱导肝细胞增殖。进一步 初步实验表明，含有CXC的非ELR 趋化因子ENA-78和MIP-2可引起肝细胞增殖。相比之下， ELR负性分子IP-10和MIG不能诱导肝细胞 扩散。进一步的初步实验表明，非ELR 含趋化因子IP-10和MIG抑制肝细胞增殖 由含有CXC趋化因子的ELR诱导。我们建议ELR 含有CXC趋化因子不仅对肝脏炎症很重要， 也是为了在受伤后启动杠杆再生，这是至关重要的 以求在急性肝脏损伤后宿主存活。我们还建议 含有CXC分子的ELR触发的肝脏有丝分裂 被含有趋化因子的非ELR抑制，并且ELR基序是 这些分子中一个诱导肝细胞死亡的关键区域 有丝分裂。我们的实验室历史上一直在研究细胞因子和 炎症反应，特别是与肝脏损伤有关的炎症反应。 这项建议是我们先前研究的合乎逻辑的延伸，涉及 肝脏炎症反应，因为它开始调查的作用 这些炎性趋化因子在整个修复过程中。这有 潜在的重要临床应用。衰弱的肝脏是唯一 我们没有机械或药理手段的重要器官 支持。通过提供对肝脏再生过程的见解， 这些研究可能会为失败的患者带来新的治疗方法 肝脏。

Inflammation is a critical component of the host response to injury and infection and is intimately tied to tissue repair and wound healing. Inflammatory mediators, such as the CXC chemokines, are essential in the response to hepatic injury. The CXC chemokines, including epithelial neutrophil activating protein (ENA-78) and macrophage inflammatory protein-2 (MIP-2), are induced by tumor necrosis factor-alpha (TNF) and are known for their neutrophil chemotactic and angiogenic properties. They are an important component of hepatic inflammation after liver injury. Some of the CXC chemokines contain a specific amino acid sequence at their amino terminal end, the ELR sequence (Glu-Leu-Arg); which define the molecule's biologic activity, specifically, neutrophil chemotaxis and angiogenesis. Other molecules in this family, including interferon-gamma- inducible protein (IP-10) and monokine induced by interferon-gamma (MIG), lack this sequence and therefore lack neutrophile chemotactic activity, are angiostatic, and inhibit angiogenesis induced ELR containing chemokines. Recent studies have demonstrated that the CXC chemokines have mitogenic effects in addition to causing angiogenesis and neutrophil chemotaxis. Experiments in our laboratory using a rat model of lobar hepatic ischemia/reperfusion have shown that TNF is released in response to hepatic ischemia/reperfusion. This TNF then triggers hepatic ENA-78 release, which is important for neutrophil influx and the development of inflammation in the injured liver. Interestingly, peak level of ENA-78 occurred at 24 hours of reperfusion, which is after the time of peak hepatic neutrophil influx. This observation, couple with the recently described angiogenic and mitogenic actions of the CXC chemokines, led us to postulate that ENA-78 was play an additional role in this model, possibly helping to initiate hepatic repair and regeneration. Our preliminary studies how that the ELR containing CXC chemokines, ENA-78 and MIP-2, cause hepatocyte proliferation. In contrast, the ELR negative molecules, IP-10 and MIG, do not induce hepatocyte proliferation. Further preliminary experiments suggests that the non-ELR containing CXC chemokines, ENA-78 and MIP-2, cause hepatocyte proliferation. In contrast, the ELR negative molecules, IP-10 and MIG, do not induce hepatocyte proliferation. Further preliminary experiments suggests that the non-ELR containing chemokines, IP-10 and MIG, inhibit hepatocyte proliferation induced by the ELR containing CXC chemokines. We propose that the ELR containing CXC chemokines are important not only for hepatic inflammation, but also for initiating lever regeneration after injury, which is crucial for host survival after an acute hepatic insult. We also propose that hepatic mitogenesis triggered by the ELR containing CXC molecules is inhibited by the non-ELR containing chemokines, and that the ELR motif is a critical region in these molecules for the induction of hepatic mitogenesis. Our laboratory has historically studied cytokines and the inflammatory response, particularly as they pertain to hepatic injury. This proposal is a logical extension of our previous studies involving the hepatic inflammatory responses as it begins to investigate the role of these inflammatory chemokines in the overall reparative process. This has potentially important clinical applications. The failing liver is the only vital organ for which we have no means of mechanical or pharmacological support. By providing insights into the hepatic regenerative process, these studies could potentially lead to novel treatments for the failing liver.