Cuschieri Joseph, Maier Ronald V
University of Washington, Department of Surgery, Seattle, Washington 98104, USA.
Antioxid Redox Signal. 2007 Sep;9(9):1485-97. doi: 10.1089/ars.2007.1670.
Oxidant stress, induced under a variety of conditions, is known to lead to the molecular reprogramming of the tissue-fixed macrophage. This reprogramming is associated with an altered response to subsequent inflammatory stimuli, such as lipopolysaccharide (LPS), leading to enhanced liberation of proinflammatory chemokines and cytokines. Due to this altered response, dysregulated immunity ensues, leading to the development of clinical syndromes such as multiple organ dysfunction syndrome (MODS). Although the mechanisms responsible for this altered macrophage activity by oxidant stress remains complex and poorly elucidated, it appears, based on recent research, that early and direct alterations within lipid rafts are responsible. This early and direct interaction with lipid rafts by oxidants leads to the mobilization of annexin VI from lipid raft constructs, leading to the release of calcium. This increased cytosolic concentration of this secondary messenger, in turn, results in the activation of calcium-dependent kinases, leading to further alterations in lipid raft lipids and eventually lipid raft proteins. Due to these lipid raft compositional changes, preassembly of receptor complexes occur, leading to enhanced proinflammatory activation. Within this review, the complexity of oxidant-induced reprogramming within the tissue fixed macrophage as currently understood is explained.
在多种条件下诱导产生的氧化应激已知会导致组织固定巨噬细胞的分子重编程。这种重编程与对后续炎症刺激（如脂多糖，LPS）的反应改变相关，从而导致促炎趋化因子和细胞因子的释放增加。由于这种反应改变，免疫调节失调随之发生，导致多器官功能障碍综合征（MODS）等临床综合征的发展。尽管氧化应激导致巨噬细胞活性改变的机制仍然复杂且尚未完全阐明，但基于最近的研究，似乎脂质筏内的早期直接改变是原因所在。氧化剂与脂质筏的这种早期直接相互作用导致膜联蛋白VI从脂质筏结构中动员出来，从而导致钙的释放。这种第二信使的胞质浓度增加进而导致钙依赖性激酶的激活，导致脂质筏脂质进一步改变，最终导致脂质筏蛋白改变。由于这些脂质筏组成的变化，受体复合物发生预组装，导致促炎激活增强。在这篇综述中，解释了目前所理解的氧化应激诱导组织固定巨噬细胞重编程的复杂性。
