Jaeschke Hartmut, Hasegawa Tadashi
Liver Research Institute, University of Arizona, College of Medicine, Tucson, AZ 85737, USA.
Liver Int. 2006 Oct;26(8):912-9. doi: 10.1111/j.1478-3231.2006.01327.x.
Hepatic infiltration of polymorphonuclear leukocytes (neutrophils) is an early response to tissue injury, cellular stress or systemic inflammation. Neutrophil activation is vital for host-defense and the removal of cell debris but can also cause additional tissue damage or even liver failure. In order to prevent the detrimental effects of neutrophils without compromising host-defense reactions, it is important to understand the mechanisms of neutrophil hepatotoxicity. The first step in the pathophysiology is the priming and recruitment of neutrophils into the liver vasculature by inflammatory mediators, e.g. cytokines, chemokines, or complement factors. Most critical for parenchymal cell damage is the accumulation in sinusoids, which does not depend on cellular adhesion molecules. The next step is the extravasation into the parenchyma. This process requires a chemotactic signal from hepatocytes or already extravasated neutrophils and depends on cellular adhesion molecules on neutrophils (beta(2) or beta(1) integrins) and on endothelial cells (intercellular or vascular cell adhesion molecules). The third step is the direct contact with target cells (hepatocytes), which involves beta(2) integrins and triggers the full activation of the neutrophil with a long-lasting adherence-dependent oxidant stress and degranulation. The oxidants diffuse into hepatocytes and trigger an intracellular oxidant stress, mitochondrial dysfunction and eventually cause oncotic necrotic cell death. Neutrophil-derived proteases facilitate extravasation and are involved in the regulation of inflammatory mediator production. Based on these mechanisms, it appears that strengthening of the intracellular defense mechanisms in hepatocytes may be the most promising therapeutic approach to selectively prevent neutrophil-mediated tissue damage without compromising their host-defense function.
多形核白细胞（中性粒细胞）的肝浸润是对组织损伤、细胞应激或全身炎症的早期反应。中性粒细胞的激活对于宿主防御和清除细胞碎片至关重要，但也可能导致额外的组织损伤甚至肝衰竭。为了在不损害宿主防御反应的情况下预防中性粒细胞的有害影响，了解中性粒细胞肝毒性的机制很重要。病理生理学的第一步是炎症介质（如细胞因子、趋化因子或补体因子）将中性粒细胞启动并募集到肝脏血管系统中。对实质细胞损伤最为关键的是在肝血窦中的积聚，这并不依赖于细胞粘附分子。下一步是向实质内渗出。这个过程需要来自肝细胞或已经渗出的中性粒细胞的趋化信号，并依赖于中性粒细胞（β(2)或β(1)整合素）和内皮细胞（细胞间或血管细胞粘附分子）上的细胞粘附分子。第三步是与靶细胞（肝细胞）直接接触，这涉及β(2)整合素，并通过持久的粘附依赖性氧化应激和脱颗粒触发中性粒细胞的完全激活。氧化剂扩散到肝细胞中并引发细胞内氧化应激、线粒体功能障碍，最终导致肿胀性坏死性细胞死亡。中性粒细胞衍生的蛋白酶促进渗出，并参与炎症介质产生的调节。基于这些机制，增强肝细胞内的防御机制似乎可能是在不损害其宿主防御功能的情况下选择性预防中性粒细胞介导的组织损伤的最有前景的治疗方法。
