Pietrangelo Antonello
Centre for the Study of Iron Disorders, Department of Internal Medicine, University of Modena and Reggio Emilia, Policlinico, Via del Pozzo 71, 41100 Modena, Italy.
Alcohol. 2003 Jun;30(2):121-9. doi: 10.1016/s0741-8329(03)00126-5.
Iron is an essential micronutrient. However, because human beings have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. Indeed, when iron-buffering capability is overwhelmed, oxidative stress-induced cell damage and fibrogenesis may arise, mainly in the liver, the main storage site for iron in the body. Results of recent studies have clearly shown that these pathologic events are induced by iron-generated reactive oxygen species and lipid peroxidation by-products. Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix components in the liver, is a dynamic process, from chronic liver damage to end-stage liver cirrhosis. Iron-induced oxidant stress is involved in this process (1) as the primary cause of parenchymal cell necrosis or (2) as activator of cells that are effectors [e.g., hepatic stellate cells, (myo)fibroblasts] or key mediators (e.g., Kupffer cells) of hepatic fibrogenesis (or through both mechanisms). Beyond their effect as direct cytotoxic agents, iron and free radicals may trigger increased synthesis of collagen in myofibroblast-like cells as well as activate granulocytes and Kupffer cells, resulting in an increased formation of cytokines and eicosanoids and further reactive oxygen species. This may constitute a cascade of amplifying loops, which perpetuate the fibrogenic process. The fibrogenic potential of iron is even more dramatic when iron acts in concert with other hepatotoxins such as alcohol. In this instance, even if tissue iron levels are only slightly elevated, the toxic effect of alcohol or its metabolites may be amplified and propagated with rapid acceleration of the liver disease. At the molecular level, the presence of catalytically active "free iron" may (1) contribute directly to the hepatotoxicity of alcohol or (2) enhance the generation of cytokine and fibrogenic mediators from resident Kupffer cells (or be involved in both ways). A challenge for future research is to develop therapeutic tools able to block "redox-active" free iron in the cell.
铁是一种必需的微量营养素。然而，由于人类无法控制铁的排泄，无论铁的进入途径如何，过量的铁都会在实质器官中蓄积，并威胁细胞的生存能力。事实上，当铁缓冲能力不堪重负时，氧化应激诱导的细胞损伤和纤维化可能会出现，主要发生在肝脏，肝脏是体内铁的主要储存部位。最近的研究结果清楚地表明，这些病理事件是由铁产生的活性氧和脂质过氧化副产物引起的。肝纤维化的特征是肝脏中细胞外基质成分过度蓄积，是一个从慢性肝损伤到终末期肝硬化的动态过程。铁诱导的氧化应激参与了这个过程：（1）作为实质细胞坏死的主要原因；（2）作为肝纤维化效应细胞（如肝星状细胞、成纤维细胞）或关键介质（如库普弗细胞）的激活剂（或通过两种机制）。除了作为直接细胞毒性剂的作用外，铁和自由基可能会触发成肌纤维细胞样细胞中胶原蛋白合成的增加，以及激活粒细胞和库普弗细胞，导致细胞因子和类花生酸以及更多活性氧的形成增加。这可能构成一系列放大循环，使纤维化过程持续下去。当铁与其他肝毒素（如酒精）协同作用时，铁的纤维化潜力更为显著。在这种情况下，即使组织铁水平仅略有升高，酒精或其代谢产物的毒性作用也可能被放大，并随着肝病的迅速加速而传播。在分子水平上，具有催化活性的“游离铁”的存在可能：（1）直接导致酒精的肝毒性；（2）增强驻留库普弗细胞中细胞因子和纤维化介质的产生（或通过两种方式参与）。未来研究的一个挑战是开发能够阻断细胞中“氧化还原活性”游离铁的治疗工具。
