Soejima K, Ishizaka A, Urano T, Sayama K, Sakamaki F, Nakamura H, Terashima T, Waki Y, Tasaka S, Fujishima S, Kawata T, Christ W J, Kanazawa M
Department of Medicine, School of Medicine, Keio University, Tokyo, Japan.
Am J Respir Crit Care Med. 1996 Oct;154(4 Pt 1):900-6. doi: 10.1164/ajrccm.154.4.8887583.
B464 is a novel synthetic analog of lipid A, a toxic component of endotoxin (LPS; lipopolysaccharide). We investigated the effects of B464 on both LPS-induced cellular responses in vitro and acute lung injury in vivo. In the in vitro study, B464 inhibited tumor necrosis factor-alpha (TNF-alpha) production from human monocytes, priming and stiffening of neutrophils, and expression of adhesion molecules on endothelial cells induced by LPS. We then studied the effects of B464 pretreatment on acute lung injury elicited by intravenous LPS administration in vivo. Guinea pigs were divided into saline control, B464 alone, LPS alone, and LPS + B464 groups. Animals were observed for 4 h after LPS administration, and lung injury was evaluated by extravascular lung water, 125I-albumin leakage in lung tissue, and lung neutrophil accumulation. In the LPS alone group, rapid and sustained peripheral neutropenia (p < 0.001 versus saline at 15 min and at 1, 2, and 4 h), an increased plasma TNF-alpha concentration (p < 0.005 at 1 h), and increases in lung injury parameters (p < 0.05) were observed. In the LPS + B464 group, no changes were observed in either plasma TNF-alpha or lung injury parameters. Transient peripheral neutropenia and subsequent rapid recovery (p > 0.05, p < 0.001, p < 0.01, and p > 0.05 at 15 min and 1, 2, and 4 h, respectively) were observed in the LPS + B464 group. These in vivo data, together with in vitro evidence of suppressed cellular responses, suggest that B464 (1) inhibits neutrophil accumulation in lung tissue, and (2) attenuates the development of acute lung injury by blocking the activation of neutrophils and mononuclear cells as well as the interaction between neutrophils and endothelial cells.
B464是脂多糖（LPS；内毒素的一种有毒成分）的一种新型合成类似物。我们研究了B464对体外LPS诱导的细胞反应以及体内急性肺损伤的影响。在体外研究中，B464抑制人单核细胞产生肿瘤坏死因子-α（TNF-α）、中性粒细胞的预激活和僵化以及LPS诱导的内皮细胞上粘附分子的表达。然后我们研究了B464预处理对体内静脉注射LPS引起的急性肺损伤的影响。豚鼠分为生理盐水对照组、单独使用B464组、单独使用LPS组和LPS + B464组。在注射LPS后观察动物4小时，并通过血管外肺水、肺组织中125I-白蛋白渗漏和肺中性粒细胞积聚来评估肺损伤。在单独使用LPS组中，观察到快速且持续的外周血中性粒细胞减少（在15分钟以及1、2和4小时时，与生理盐水组相比p < 0.001）、血浆TNF-α浓度升高（在1小时时p < 0.005）以及肺损伤参数增加（p < 0.05）。在LPS + B464组中，血浆TNF-α或肺损伤参数均未观察到变化。在LPS + B464组中观察到短暂的外周血中性粒细胞减少及随后的快速恢复（分别在15分钟以及1、2和4小时时p > 0.05、p < 0.001、p < 0.01和p > 0.05）。这些体内数据，连同体外细胞反应受抑制的证据，表明B464（1）抑制肺组织中的中性粒细胞积聚，并且（2）通过阻断中性粒细胞和单核细胞的激活以及中性粒细胞与内皮细胞之间的相互作用来减轻急性肺损伤的发展。
