Chow C W, Grinstein S, Rotstein O D
Department of Medicine, University of Toronto, ON, Canada.
New Horiz. 1995 May;3(2):342-51.
The cellular signaling events leading to the systemic inflammatory response syndrome and sepsis in monocytes/macrophages activated by lipopolysaccharide (LPS) are well understood. LPS is a glycolipid component of Gram-negative bacterial cell wall. It exerts its effect through the lipid A moiety. LPS binds to monocytes/macrophages via a membrane-bound receptor, CD14, an interaction which is optimized in the presence of plasma factors, LPS-binding protein, and septin. Although LPS is known to bind to other receptors, the roles of these receptors in transmembrane signaling and activation of monocytes/macrophages are not as well understood as is that of the CD14 receptor. Intracellular events in response to LPS stimulation are mediated by phospholipase (PL) C, protein kinases, PLA2, and PLD. Activation of PLC by LPS results in the release of diacylglycerol and inositol 1,4,5-trisphosphate. The former mediates the stimulation of protein kinase C, and the latter induces an increase in intracellular calcium concentration. LPS stimulation of monocytes/macrophages also results in the phosphorylation and activation of several protein kinases, including protein tyrosine kinases which mediate cytokine production, and mitogen-activated protein kinase which activates cytosolic PLA2 to release arachidonate. LPS also plays a role in cellular proliferation and differentiation. Upregulation of the secretory form of PLA2 has also been documented in response to LPS. PLD is stimulated by LPS to release phosphatidic acid (PA). PA can activate the respiratory burst by increasing diacylglycerol production and by modulating the effects of guanine nucleotide-binding proteins. Therapeutic strategies to decrease the clinical effects of sepsis would logically include agents which block at initial receptor-ligand interaction, as well as those which attenuate the intracellular events that follow LPS stimulation. Early in vivo studies are promising, but clearly much work remains to be done.
脂多糖（LPS）激活单核细胞/巨噬细胞导致全身炎症反应综合征和脓毒症的细胞信号传导事件已得到充分了解。LPS是革兰氏阴性菌细胞壁的糖脂成分。它通过脂质A部分发挥作用。LPS通过膜结合受体CD14与单核细胞/巨噬细胞结合，在血浆因子、LPS结合蛋白和septin存在的情况下，这种相互作用得到优化。尽管已知LPS可与其他受体结合，但这些受体在单核细胞/巨噬细胞跨膜信号传导和激活中的作用不如CD14受体那样被充分理解。对LPS刺激的细胞内事件由磷脂酶（PL）C、蛋白激酶、PLA2和PLD介导。LPS激活PLC会导致二酰基甘油和肌醇1,4,5-三磷酸的释放。前者介导蛋白激酶C的刺激，后者诱导细胞内钙浓度升高。LPS刺激单核细胞/巨噬细胞还会导致几种蛋白激酶的磷酸化和激活，包括介导细胞因子产生的蛋白酪氨酸激酶，以及激活胞质PLA2以释放花生四烯酸的丝裂原活化蛋白激酶。LPS在细胞增殖和分化中也起作用。响应LPS，也有分泌型PLA2上调的记录。LPS刺激PLD释放磷脂酸（PA）。PA可通过增加二酰基甘油的产生和调节鸟嘌呤核苷酸结合蛋白的作用来激活呼吸爆发。降低脓毒症临床影响的治疗策略在逻辑上应包括阻断初始受体-配体相互作用的药物，以及减弱LPS刺激后细胞内事件的药物。早期的体内研究很有前景，但显然仍有许多工作要做。
