*Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee; †Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas; and ‡School of Medicine, The University of Tennessee Health Science Center, Memphis; and §Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Shock. 2013 Dec;40(6):451-62. doi: 10.1097/SHK.0000000000000042.
Lipopolysaccharide (LPS, endotoxin) is a structural component of the gram-negative outer membrane. The lipid A moiety of LPS binds to the LPS receptor complex expressed by leukocytes, endothelial cells, and parenchymal cells and is the primary component of gram-negative bacteria that is recognized by the immune system. Activation of the LPS receptor complex by native lipid A induces robust cytokine production, leukocyte activation, and inflammation, which is beneficial for clearing bacterial infections at the local level but can cause severe systemic inflammation and shock at higher challenge doses. Interestingly, prior exposure to LPS renders the host resistant to shock caused by subsequent LPS challenge, a phenomenon known as endotoxin tolerance. Treatment with lipid A has also been shown to augment the host response to infection and to serve as a potent vaccine adjuvant. However, the adverse effects associated with the pronounced inflammatory response limit the use of native lipid A as a clinical immunomodulator. More recently, analogs of lipid A have been developed that possess attenuated proinflammatory activity but retain attractive immunomodulatory properties. The lipid A analog monophosphoryl lipid A exhibits approximately 1/1,000th of the toxicity of native lipid A but retains potent immunoadjuvant activity. As such, monophosphoryl lipid A is currently used as an adjuvant in several human vaccine preparations. Because of the potency of lipid A analogs as immunoadjuvants, numerous laboratories are actively working to identify and develop new lipid A mimetics and to optimize their efficacy and safety. Based on those characteristics, lipid A analogs represent an attractive family of immunomodulators.
脂多糖（LPS，内毒素）是革兰氏阴性外膜的结构组成部分。LPS 的脂质 A 部分与白细胞、内皮细胞和实质细胞表达的 LPS 受体复合物结合，是免疫系统识别的革兰氏阴性细菌的主要成分。天然脂质 A 激活 LPS 受体复合物会诱导强烈的细胞因子产生、白细胞激活和炎症，这有利于在局部清除细菌感染，但在更高的挑战剂量下会导致严重的全身炎症和休克。有趣的是，先前暴露于 LPS 会使宿主对随后的 LPS 挑战引起的休克产生抗性，这种现象称为内毒素耐受。用脂质 A 治疗也已被证明可增强宿主对感染的反应，并作为有效的疫苗佐剂。然而，与强烈炎症反应相关的不良反应限制了天然脂质 A 作为临床免疫调节剂的使用。最近，已经开发出了具有减弱的促炎活性但保留有吸引力的免疫调节特性的脂质 A 类似物。单磷酰脂质 A 具有天然脂质 A 毒性的约 1/1000，但保留有效的免疫佐剂活性。因此，单磷酰脂质 A 目前被用作几种人类疫苗制剂的佐剂。由于脂质 A 类似物作为免疫佐剂的效力，许多实验室正在积极努力鉴定和开发新的脂质 A 模拟物，并优化它们的功效和安全性。基于这些特性，脂质 A 类似物代表了一类有吸引力的免疫调节剂。
