Involvement of high mobility group box 1 and the therapeutic effect of recombinant thrombomodulin in a mouse model of severe acute respiratory distress syndrome.
Involvement of high mobility group box 1 and the therapeutic effect of recombinant thrombomodulin in a mouse model of severe acute respiratory distress syndrome.
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DOI：
10.1111/cei.12106
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发表时间：
2013-08
影响因子：
4.6
通讯作者：
Kawakami K
中科院分区：
文献类型：
--
作者：
Kudo D;Toyama M;Aoyagi T;Akahori Y;Yamamoto H;Ishii K;Kanno E;Maruyama R;Kaku M;Kushimoto S;Kawakami K
急性呼吸窘迫综合征（Acute respiratory distress syndrome， ARDS）是由多种疾病引起的严重肺部炎症。尽管症状严重，但治疗策略一直无效。高迁移率组框1 （HMGB1）最初被认为是一种DNA结合蛋白，现已被认为是急性肺损伤的介质。重组血栓调节蛋白（rTM）除了具有抗凝血活性外，还具有通过中和HMGB1来抑制炎症反应的能力。据报道，肺中的T调节性（Treg）细胞在急性肺损伤的解决过程中改变先天免疫反应。在本研究中，我们研究了rTM在严重ARDS小鼠模型中的治疗作用，以及Treg细胞在这种作用中的作用。C57BL/6小鼠连续气管内注射α-半乳糖神经酰胺（α-GalCer）和脂多糖（LPS），导致严重ARDS的发生。与单独接受LPS治疗的小鼠相比，ARDS小鼠肺部HMGB1水平升高。HMGB1在肺浸润性中性粒细胞和巨噬细胞中表达。与单独LPS处理的小鼠相比，ARDS小鼠肺部Treg细胞明显减少。rTM治疗延长了ARDS患者的生存时间，改善了ARDS的发展，这与肺中Treg细胞和白细胞介素(IL)-10和转化生长因子(TGF)-β的合成增加有关。这些结果表明，HMGB1参与了严重ARDS的发生发展，rTM通过促进炎症部位Treg细胞的积累而发挥治疗作用。
Acute respiratory distress syndrome (ARDS) is accompanied by severe lung inflammation induced by various diseases. Despite the severity of the symptoms, therapeutic strategies have been ineffective. High mobility group box 1 (HMGB1), which was identified originally as a DNA binding protein, has been proposed as a mediator of acute lung injury. In addition to its anti-coagulant activity, recombinant thrombomodulin (rTM) possesses an ability to suppress the inflammatory response through neutralizing HMGB1. T regulatory (Treg) cells in the lungs are reported to modify innate immune responses during resolution of acute lung injury. In the present study, we investigated the therapeutic effect of rTM, and the contribution of Treg cells to this effect, in a mouse model of severe ARDS. C57BL/6 mice received sequential intratracheal administration of α-galactosylceramide (α-GalCer) and lipopolysaccharide (LPS), which resulted in the development of severe ARDS. HMGB1 levels in the lungs increased to a higher level in ARDS mice compared to those in mice treated with LPS alone. HMGB1 was expressed in the infiltrating neutrophils and macrophages in lungs. Treg cells were reduced significantly in the lungs of ARDS mice compared to those in mice treated with LPS alone. rTM administration prolonged the survival time and ameliorated the development of ARDS, which was associated with increased Treg cells and synthesis of interleukin (IL)-10 and transforming growth factor (TGF)-β in the lungs. These results suggest that HMGB1 is involved in the development of severe ARDS and rTM shows therapeutic effects through promoting the accumulation of Treg cells at the inflammatory sites.
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影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
4.3
作者：
Bastarache, Julie A.;Blackwell, Timothy S.
通讯作者：
Blackwell, Timothy S.
DOI：
10.1152/ajplung.00359.2004
发表时间：
2005-05-01
影响因子：
4.9
作者：
Kim, JY;Park, JS;Abraham, E
通讯作者：
Abraham, E
白介素10可保护小鼠免受致命性内毒素血症的侵害。
影响因子：
15.3
作者：
Howard, M;Muchamuel, T;Andrade, S;Menon, S
通讯作者：
Menon, S
DOI：
10.1073/pnas.95.10.5690
发表时间：
1998-05-12
影响因子：
11.1
作者：
Kawano, T;Cui, JQ;Taniguchi, M
通讯作者：
Taniguchi, M