Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions
Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions
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DOI：
10.1152/ajpgi.00568.2005
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发表时间：
2006-06-01
影响因子：
4.5
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Jaeschke, Hartmut
在包括肝脏在内的许多器官中，多形核白细胞（中性粒细胞）是对微生物感染和组织创伤（如缺血再灌注损伤）的先天免疫反应的重要组成部分。然而，过度的炎症反应会导致现有损伤的急剧恶化。为了设计干预措施，有选择地针对中性粒细胞的有害影响，详细了解病理生理学是至关重要的。全身或局部暴露于促炎介质会激活和启动中性粒细胞形成活性氧，并将其招募到肝脏的血管床，而不会造成组织损伤。然而，从实质产生趋化信号会引发外渗和对靶细胞（如肝细胞）的攻击。与靶标的粘附诱导脱粒，释放蛋白酶，形成活性氧，包括过氧化氢和次氯酸，这些活性氧可以扩散到肝细胞中，诱导细胞内氧化应激和线粒体功能障碍。各种中性粒细胞衍生的蛋白酶参与转运和细胞毒性，但也可以通过加工促炎介质促进炎症反应。此外，坏死细胞释放介质，如高迁移率组盒-1，进一步促进中性粒细胞肝炎和组织损伤。基于对中性粒细胞介导的肝损伤机制的这些不断发展的见解，最具选择性的策略似乎不会干扰中性粒细胞的细胞毒性潜力，而是加强靶细胞的防御机制，包括增强细胞内抗氧化防御系统，激活细胞存活途径，或启动细胞周期激活和再生。
Polymorphonuclear leukocytes (neutrophils) are a vital part of the innate immune response to microbial infections and tissue trauma, e. g., ischemia-reperfusion injury, in many organs including the liver. However, an excessive inflammatory response can lead to a dramatic aggravation of the existing injury. To design interventions, which selectively target the detrimental effects of neutrophils, a detailed understanding of the pathophysiology is critical. Systemic or local exposure to proinflammatory mediators causes activation and priming of neutrophils for reactive oxygen formation and recruits them into the vascular beds of the liver without causing tissue injury. However, generation of a chemotactic signal from the parenchyma will trigger extravasation and an attack on target cells (e. g., hepatocytes). Adhesion to the target induces degranulation with release of proteases and formation of reactive oxygen species including hydrogen peroxide and hypochlorous acid, which can diffuse into hepatocytes and induce an intracellular oxidant stress and mitochondrial dysfunction. Various neutrophil-derived proteases are involved in transmigration and cell toxicity but can also promote the inflammatory response by processing of proinflammatory mediators. In addition, necrotic cells release mediators, e. g., high-mobility group box-1, which further promotes neutrophilic hepatitis and tissue damage. On the basis of these evolving insights into the mechanisms of neutrophil-mediated liver damage, the most selective strategies appear not to interfere with the cytotoxic potential of neutrophils, but rather strengthen the target cells' defense mechanisms including enhancement of the intracellular antioxidant defense systems, activation of cell survival pathways, or initiation of cell cycle activation and regeneration.