Activation of the innate immune system and alcoholic liver disease: Effects of ethanol per se or enhanced intestinal translocation of bacterial toxins induced by ethanol?
Activation of the innate immune system and alcoholic liver disease: Effects of ethanol per se or enhanced intestinal translocation of bacterial toxins induced by ethanol?
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DOI：
10.1097/01.alc.0000189280.19073.28
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发表时间：
2005-11-01
影响因子：
3.2
通讯作者：
Bode, JC
中科院分区：
文献类型：
--
作者：
Bode, C;Bode, JC
一般认为，先天免疫系统的激活和促炎细胞因子和其他介质的释放增加在酒精性肝病（ALD）的发展中起重要作用。然而，乙醇诱导的单核细胞/巨噬细胞（包括库普弗细胞）活化中涉及的机制仍然是一个争论的问题。简要回顾将总结文献中已发表的关于两种主要病理机制的数据：I）肠源性细菌毒素，特别是内毒素;和II）酒精氧化诱导的代谢变化（独立于机制I）。对于病理机制I，许多研究组已经发表了明确的证据：酒精诱导上胃肠道粘膜损伤，并导致肠粘膜对大分子（如内毒素）的渗透性显著增加。所产生的内毒素血症然后导致枯否细胞和其他巨噬细胞的活化。促炎介质的释放增加（例如，TNF-α，II-1，反应氧类）和其它炎性细胞（例如，中性粒细胞）最终导致肝损伤。关于第二种病理机制，已经反复论证了通过对大鼠或小鼠长期给予乙醇诱导的代谢改变可能增加单核细胞/巨噬细胞分泌TNF-α和其他促炎介质的敏感性，从而增加对乙醇诱导的肝损伤的易感性。然而，在所有的喂养实验中，乙醇对肠道通透性和细菌毒素（内毒素）的增强易位的影响可能会发生（或至少不能排除）。后者也适用于使用来自乙醇喂养动物的分离的巨噬细胞/枯否细胞的实验。因此，为了澄清与乙醇代谢相关的改变（乙醇的“直接”作用）是否有助于激活先天免疫系统，需要使用无菌动物进行研究，以排除乙醇通过肠道衍生细菌毒素产生的“间接”作用。
It is generally accepted that activation of the innate immune system and increased release of proinflammatory cytokines and other mediators plays an important role in the development of alcoholic liver disease (ALD). The mechanisms involved in the ethanol-induced activation of monocytes/macrophages (including Kupffer cells) are however, still a matter of debate. The brief review will summarize the published data from the literature on the two main pathomechanisms discussed until now: I) Gut-derived bacterial toxins, specially endotoxin; and II) metabolic changes induced by alcohol oxidation (independent of mechanism I). For pathomechanism I, clear evidence has been published from numerous groups: Alcohol induces mucosal injury in the upper gastrointestinal tract and leads to marked increase in the permeability of the gut mucosa to macromolecules such as endotoxin. The resulting endotoxemia then leads to activation of Kupffer cells and other macrophages. The increased release of pro-inflammatory mediators (e.g., TNF-alpha, II-1, reacting oxygen species) and infiltration of other inflammatory cells (e.g., neutrophils) finally causes liver damage. Regarding the second pathomechanism it has repeatedly been argued that the metabolic alterations which are induced by chronic administration of ethanol to rats or mice might increase the sensitivity of monocytes/macrophages to secrete TNF-alpha and other pro-inflammatory mediators thereby increasing the susceptibility to ethanol-induced liver injury. However, in all feeding experiments the effect of ethanol on intestinal permeability and enhanced translocation of bacterial toxins (endotoxin) is likely to occur (or at least cannot be excluded). The latter holds true also for experiments using isolated macrophages/Kupffer cells from ethanol fed animals. Therefore, to clarify whether or not alterations related to ethanol metabolism ("direct" effects of ethanol) contribute to the activation of the innate immune system studies using germ-free animals are needed to exclude the "indirect" effect of ethanol via gut-derived bacterial toxins.