SYSTEMIC INVOLVEMENT OF HIGH-MOBILITY GROUP BOX 1 PROTEIN AND THERAPEUTIC EFFECT OF ANTI-HIGH-MOBILITY GROUP BOX 1 PROTEIN ANTIBODY IN A RAT MODEL OF CRUSH INJURY
SYSTEMIC INVOLVEMENT OF HIGH-MOBILITY GROUP BOX 1 PROTEIN AND THERAPEUTIC EFFECT OF ANTI-HIGH-MOBILITY GROUP BOX 1 PROTEIN ANTIBODY IN A RAT MODEL OF CRUSH INJURY
复制标题
DOI：
10.1097/shk.0b013e31824ed6b7
复制
发表时间：
2012-06-01
期刊：
影响因子：
3.1
通讯作者：
Shimazu, Takeshi
中科院分区：
文献类型：
--
作者：
Shimazaki, Junya;Matsumoto, Naoya;Shimazu, Takeshi
挤压伤患者常出现全身炎症反应综合征，并发生多器官功能衰竭。局部组织损伤引起远端器官衰竭的机制尚不清楚。高迁移率族蛋白1（HMGB 1）是挤压伤中引起全身炎症反应的损伤相关分子模式之一。我们研究了挤压伤大鼠模型中HMGB 1的参与和抗HMGB 1抗体治疗的效果。大鼠双后肢压迫6 h后松解。挤压伤组大鼠血清HMGB 1水平在释放压力后3 h达到峰值，随后血清IL-6和TNF-α水平升高。苏木精-伊红染色显示挤压伤后24 h肺实质性损伤，免疫组化分析显示晚期糖基化终产物受体表达上调。静脉注射抗HMGB 1抗体可改善存活率（每组n = 20），并显著抑制HMGB 1、白细胞介素6和肿瘤坏死因子的血清水平。与挤压伤未处理组（每组n = 6-9）比较。肺损伤的组织学发现得到改善，并且治疗阻碍了晚期糖基化终产物受体的表达。这些结果表明HMGB 1在挤压损伤后立即释放，并作为促炎介质。施用抗HMGB 1抗体通过阻断细胞外HMGB 1减少炎症反应并改善存活。因此，HMGB 1似乎是一个治疗靶点，抗HMGB 1抗体可能成为一种有前途的抗挤压伤的新疗法，以防止进展为多器官功能衰竭。
Patients with crush injury often present systemic inflammatory response syndrome and fall into multiple organ failure. The mechanism by which the local tissue damage induces distant organ failure is still unclear. We focused on high-mobility group box 1 protein (HMGB1) as one of the damage-associated molecular pattern molecules that cause systemic inflammation in crush injury. We investigated involvement of HMGB1 and the effects of treatment with anti-HMGB1 antibody in a rat model of crush injury. Both hindlimbs of rats were compressed for 6 h and then released. In the crush injury group, the level of serum HMGB1 peaked at 3 h after releasing compression, followed by the increasing in the serum levels of interleukin 6 and tumor necrosis factor alpha. Hematoxylin-eosin staining showed substantial damage in the lung 24 h after the crush injury, with upregulation of the expression of receptor for advanced glycation end products, as revealed by immunohistochemical analysis. Intravenous administration of anti-HMGB1 antibody improved survival (n = 20 each group) and significantly suppressed serum levels of HMGB1, interleukin 6, and tumor necrosis factor ! compared with the untreated crush injury group (n = 6-9 each group). Histological findings of lung damage were ameliorated, and the expression of receptor for advanced glycation end products was hampered by the treatment. These results indicate that HMGB1 is released in response to damage immediately after crush injury and acts as a proinflammatory mediator. Administration of anti-HMGB1 antibody reduced inflammatory reactions and improved survival by blocking extracellular HMGB1. Thus, HMGB1 appears to be a therapeutic target, and anti-HMGB1 antibody may become a promising novel therapy against crush injury to prevent the progression to multiple organ failure.