CXC CHEMOKINES AND LIVER REGENERATION

炎症是宿主对损伤的反应的关键组成部分， 感染并且与组织修复和伤口愈合密切相关。 炎症介质，如CXC趋化因子，在炎症过程中是必不可少的。 对肝损伤的反应。CXC趋化因子，包括上皮细胞 中性粒细胞活化蛋白（ENA-78）与巨噬细胞炎性 蛋白-2（MIP-2）由肿瘤坏死因子-α（TNF）诱导， 以其嗜中性粒细胞趋化性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趋化因子在它们的氨基酸序列中含有特定的氨基酸序列。 氨基末端，ELR序列（Glu-Leu-Arg）;其定义了 分子的生物活性，特别是中性粒细胞趋化性， 血管生成这个家族中的其他分子，包括干扰素-γ- 诱导蛋白（IP-10）和γ-干扰素（IFN-γ）诱导的单核因子， 缺乏该序列并因此缺乏嗜中性粒细胞趋化活性， 抑制血管生成，并抑制血管生成诱导的ELR， 趋化因子最近的研究表明，CXC趋化因子具有 除了引起血管生成和中性粒细胞外， 趋化性本实验采用大鼠大叶性甲状腺肿模型， 肝缺血/再灌注已经表明，TNF作为响应而释放 肝脏缺血/再灌注。这种TNF然后触发肝脏ENA-78 释放，这是重要的中性粒细胞流入和发展， 在受伤的肝脏炎症。有趣的是，ENA-78的峰值水平 发生在再灌注24小时，即峰值时间之后 肝脏中性粒细胞流入。这一观察，加上最近 描述了CXC趋化因子的血管生成和促有丝分裂作用， 假设ENA-78在这个模型中起着额外作用， 可能有助于启动肝脏修复和再生。我们 初步研究了含有CXC趋化因子ENA-78和 MIP-2引起肝细胞增殖。相反，ELR阴性 分子IP-10和IFN-γ不诱导肝细胞增殖。进一步 初步实验表明，不含ELR的CXC 趋化因子ENA-78和MIP-2引起肝细胞增殖。与此相反， ELR阴性分子IP-10和IL 10不诱导肝细胞 增殖进一步的初步实验表明，非ELR 含有趋化因子IP-10和IL-10，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趋化因子的蛋白质不仅对肝脏炎症很重要， 也可以在受伤后启动杠杆再生，这是至关重要的 急性肝损伤后宿主的存活率。我们亦建议 由含有CXC分子的ELR触发的肝有丝分裂发生， 被不含ELR的趋化因子抑制，并且ELR基序是 这些分子中诱导肝细胞凋亡的关键区域 有丝分裂我们的实验室历来研究细胞因子和 炎症反应，特别是与肝损伤有关。 这一建议是我们以前研究的逻辑延伸， 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的作用。这 潜在的重要临床应用。衰竭的肝脏是唯一 我们没有机械或药物手段的重要器官 支持.通过提供对肝脏再生过程的见解， 这些研究可能会导致新的治疗失败， 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.