创伤后内毒素增敏效应在多器官损害中的作用

The significance of lipopolysaccharidebinding protein and lipopolysaccharide receptor CD14 in increasing sensitivity to endotoxin response and multiple organ damage following trauma

目的：探讨内毒素增敏系统——脂多糖结合蛋白（ＬＢＰ）和脂多糖受体（ＣＤ１４）在严重创伤后内毒素血症诱发多器官损害中的作用及其分子机制。方法：采用低血容量创伤性休克、重度低血容量性休克、肠缺血再灌注损伤、３５％Ⅲ度烫伤等动物模型，从不同层次观察ＬＢＰ／ＣＤ１４系统的变化规律及其与多器官损害的关系。同时，结合多发伤、大面积烧伤等临床病例进行前瞻性研究。结果：急性烫伤和休克的打击可导致内毒素易位，并明显上调机体主要脏器ＬＢＰ／ＣＤ１４ｍＲＮＡ的广泛表达，腹腔巨噬细胞ＣＤ１４ｍＲＮＡ表达亦显著增强（Ｐ＜０．０５或Ｐ＜０．０１）。早期拮抗肠源性内毒素易位，可明显抑制ＬＢＰ／ＣＤ１４ｍＲＮＡ表达上调和减轻机体病理生理异常改变。临床资料显示，多发伤、休克早期血浆ＬＢＰ水平即迅速升高；严重烧伤后第７日患者血清可溶性ＣＤ１４含量亦明显上升，其中以出现多器官损害者改变尤为显著（Ｐ＜０．０５或Ｐ＜０．０１）。结论：肠源性内毒素经上调的ＬＢＰ／ＣＤ１４系统介导刺激机体产生细胞因子等炎性介质。

Objective:To investigative the potential role of lipopolysaccharidebinding protein (LBP) and lipopolysaccharide receptor CD14 in the pathogenesis of endotoxemiamediated multiple organ dysfunction syndrome (MODS) following severe trauma.Methods:Animals were subjected to hypovolemictraumatic shock,prolonged hemorrhagic shock (4 0 kPa～4 7 kPa,180 minutes),intestinal ischemiareperfusion,and 35% body surface area fullthickness thermal injury.Also,our prospective studies included patients with extensive burns,polytrauma,and healthy volunteers who served as a comparison group.Plasma endotoxin and LBP/sCD14 levels,tissue LBP/CD14 mRNA expression,and morphological evaluation were determined in these studies.Results:It was found that endotoxin levels both in tissue and plasma increased markedly after acute insults.Similarly,LBP/CD14 mRNA was expressed in various organs together with upregulation of CD14 mRNA in peritoneal macrophages.Treatment with an novel antiendotoxin agenta recombinant bactericidal/permeabilityincreasing protein,however,resulted in a significant reduction in endotoxin levels,and markedly inhibited tissue LBP/CD14 mRNA expression in various organs secondary to hemorrhage and burns ( P <0 05 or P <0 01).On the other hand,it was observed that plasma LBP levels in polytrauma patients increased during the early stages following injuries,which were significantly correlated with plasma endotoxin levels.Compared to the healthy volunteers,a significant increase in serum sCD14 levels was observed in 22 patients on day 7 postburn,and serum sCD14 levels were significantly higher in MODS group than in nonMODS group on days 7,14,and 21 postburn ( P <0 05 or P <0 01).Conclusions:Upregulation of LBP/CD14 gene expression may enhance synthesis and release of proinflammatory mediators,including tumor necrosis factor,stimulated by endogenous endotoxin translocation,and it could be one of the major molecular mechanisms with regard to increasing sensitivity to endotoxin response and development of MODS associated with severe trauma.