Fang Wen-Hui, Yao Yong-Ming, Shi Zhi-Guo, Yu Yan, Wu Ye, Lu Lian-Rong, Sheng Zhi-Yong
The Department of Microbiology and Immunology, Trauma Research Center, Postgraduate Medical College, Beijing, People's Republic of China.
Shock. 2002 Apr;17(4):329-33. doi: 10.1097/00024382-200204000-00016.
There has been a widespread impression that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mediate the toxicity of high doses of lipopolysaccharide (LPS, endotoxin) and are key factors in septic shock. However, the clinical efficacy of treatment with antagonists of TNF-alpha and IL-1beta is still controversial, suggesting that mediators other than TNF-alpha and IL-1beta might contribute causally to endotoxin-induced death. Recent studies implicated high mobility group-1 (HMG-1) protein as a late mediator of endotoxin lethality in mice. However, the role of HMG-1 in mediating multiple organ damage-associating trauma has not been studied. This study was designed to investigate changes in HMG-1 gene expression in vital organs, and its potential role in mediating multiple organ damage following major burns. Wistar rats were subjected to a 35 percent full-thickness thermal injury, and randomly divided into three groups as follows: normal controls (n = 7), thermal injury (n = 24), and recombinant bactericidal/permeability-increasing protein (rBPI21) treatment (n = 12). Tissue samples from liver and lungs were collected to measure tissue endotoxin levels and HMG-1 mRNA expression. In addition, blood samples were obtained for measurement of organ function parameters. Our data demonstrated a significant increase in HMG-1 gene expression in tissues at 24 h postburn, which remained markedly elevated up to 72 h after thermal injury (P< 0.05-0.01). Treatment with rBPI21 could significantly decrease tissue HMG-1 mRNA expression in the liver and lung (P < 0.01). In addition, there were high positive correlations between hepatic HMG-1 mRNA and serum aminoleucine transferase (ALT) and aspartate aminotransferase (AST) levels, and also between pulmonary HMG-1 mRNA and myeloperoxidase activities (P < 0.05-0.01). Taken together, these findings indicate that thermal injury per se can markedly enhance HMG-1 gene expression in various organs. Up-regulation of HMG-1 expression may be involved in the pathogenesis of endogenous endotoxin-mediated multiple organ damage secondary to major burns.
人们普遍认为，肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）介导高剂量脂多糖（LPS，内毒素）的毒性，并且是脓毒症休克的关键因素。然而，TNF-α和IL-1β拮抗剂治疗的临床疗效仍存在争议，这表明除TNF-α和IL-1β之外的介质可能在内毒素诱导的死亡中起因果作用。最近的研究表明，高迁移率族蛋白-1（HMG-1）是小鼠内毒素致死性的晚期介质。然而，HMG-1在介导多器官损伤相关创伤中的作用尚未得到研究。本研究旨在调查重要器官中HMG-1基因表达的变化，及其在严重烧伤后介导多器官损伤中的潜在作用。将Wistar大鼠进行35%全层热损伤，并随机分为三组：正常对照组（n = 7）、热损伤组（n = 24）和重组杀菌/通透性增加蛋白（rBPI21）治疗组（n = 12）。收集肝脏和肺的组织样本以测量组织内毒素水平和HMG-1 mRNA表达。此外，采集血液样本以测量器官功能参数。我们的数据表明，烧伤后24小时组织中HMG-1基因表达显著增加，直至热损伤后72小时仍显著升高（P<0.05 - 0.01）。rBPI21治疗可显著降低肝脏和肺组织中HMG-1 mRNA表达（P < 0.01）。此外，肝脏HMG-1 mRNA与血清氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平之间，以及肺组织HMG-1 mRNA与髓过氧化物酶活性之间存在高度正相关（P < 0.05 - 0.01）。综上所述，这些发现表明热损伤本身可显著增强各器官中HMG-1基因表达。HMG-1表达上调可能参与严重烧伤后继发的内毒素介导的多器官损伤的发病机制。
