Therapeutic potential of recombinant thrombomodulin for lung injury after pneumonectomy via inhibition of high-mobility group box 1 in mice.
Therapeutic potential of recombinant thrombomodulin for lung injury after pneumonectomy via inhibition of high-mobility group box 1 in mice.
复制标题
重组血栓调节蛋白通过抑制小鼠高迁移率组框 1 对肺切除术后肺损伤的治疗潜力。
DOI：
10.1097/ta.0000000000001208
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Kawamura M.
中科院分区：
文献类型：
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作者：
Takahashi Y;Matsutani N;Dejima H;Nakayama T;Okamura R;Uehara H;Kawamura M.
外科急性呼吸窘迫综合征（ARDS）是一种非常严重的疾病，可能发生在肺切除术后。尽管微创外科手术和治疗管理的进展，这种疾病的预后仍然很差。在这项研究中，我们研究了高迁移率族蛋白1（HMGB 1）在外科手术的ARDS模型中的作用，并评估了重组血栓调节蛋白（rTM）对外科手术的ARDS.METHODSC57BL/6 J小鼠进行左肺切除术的可能的治疗作用。术前12小时注射rTM，术后3天注射12小时。术后2小时给予脂多糖（LPS）。我们进行了组织学分析，并在肺切除术后第3天测定了支气管肺泡灌洗液中的HMGB 1、IL-6、IL-1β和TNF-α。在组织学分析中，左肺切除术后给予LPS诱导了严重的炎性细胞浸润和肺泡壁充血伴出血。rTM给药挽救了这些组织学变化。肺切除术后支气管肺泡灌洗液中HMGB 1、IL-6、IL-1β和TNF-α的水平在LPS给药后显著升高，而在LPS和肺切除术后给予rTM显著降低（p< 0.001）。此外，单独LPS组与肺切除术（PNX）组相比，HMGB 1或促炎细胞因子水平无统计学差异。结论左全肺切除术后应用SLPS可导致严重的肺损伤。PNX和LPS对该模型的作用相似，可能在此过程中起协同作用。rTM可能通过抑制左肺切除术后LPS诱导的HMGB 1和促炎细胞因子的分泌而对外科ARDS具有潜在的治疗作用。
BACKGROUNDSurgical acute respiratory distress syndrome (ARDS) is an extremely critical condition which may occur after major lung resection. Despite advances in minimally invasive surgical procedures and progress in the therapeutic management of this disease, prognosis remains poor. In this study, we investigated the contribution of high-mobility group box 1 (HMGB1) in a surgical ARDS model and evaluated the possible therapeutic effect of recombinant thrombomodulin (rTM) for the treatment of surgical ARDS.METHODSC57BL/6J mice underwent left pneumonectomy. rTM was injected at 12 hours before surgery, followed by 12 hours for 3 days after surgery. Lipopolysaccharide (LPS) was administered at 2 hours after surgery. We conducted a histologic analysis and measured HMGB1, IL-6, IL-1β, and TNF-α in bronchoalveolar lavage fluid on day 3 after pneumonectomy. Data were compared between the treatment groups.RESULTSOn histologic analysis, left pneumonectomy followed by LPS administration induced both severe inflammatory cellular infiltration and alveolar wall congestion with hemorrhage. rTM administration rescued these histologic changes. The level of HMGB1, IL-6, IL-1β, and TNF-α in bronchoalveolar lavage fluid was significantly increased by LPS administration after pneumonectomy and significantly decreased by rTM administration with LPS and pneumonectomy (p< 0.001). Also, LPS alone showed no statistical differences in HMGB1 or proinflammatory cytokine level compared with pneumonectomy (PNX) group. In addition, the survival outcome was also improved by rTM administration.CONCLUSIONSLPS administration after left pneumonectomy could induce the severe lung injury. PNX and LPS have similar contribution to this model and may play a synergistic role in this process. rTM may have the potential therapeutic effect for surgical ARDS via suppression of HMGB1 and the secretion of proinflammatory cytokines induced by the administration of LPS after left pneumonectomy.