The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy
The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy
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DOI：
10.1038/ki.2014.62
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发表时间：
2014-08-01
影响因子：
19.6
通讯作者：
Noiri, Eisei
中科院分区：
文献类型：
--
作者：
Doi, Kent;Ishizu, Tomoko;Noiri, Eisei
急性肺损伤和急性肾损伤是危重病患者的严重并发症，并协同增加重症监护病房的死亡率。肾和肺之间的器官串扰最近被认为是放大了每个器官的损伤。在这里，我们试图通过小鼠双侧肾切除模型来确定急性肾损伤导致急性肺损伤的可能机制。Toll样受体4(Toll样受体4，TLR4)突变型C3H/HeJ小鼠与TLR4野生型C3H/HEN小鼠相比，术后6h对双侧肾切除所致的肺损伤具有更强的抵抗力，包括中性粒细胞浸润、中性粒细胞弹性蛋白酶活性升高和血管通透性。高迁移率族蛋白B1(HMGB1)是TLR4的激动剂之一。双侧肾切除后血药浓度显著升高。用中和抗体阻断HMGB1可减少TLR4野生型C3H/HEN小鼠中性粒细胞的浸润，但对TLR4突变型C3H/HeJ小鼠无明显影响。然而，在肾缺血再灌注模型中阻断HMGB1可减少非TLR4独立的肺中性粒细胞的浸润。因此，HMGB1-TLR4途径的增强参与了双侧肾切除所致的肺损伤，而另一种HMGB1依赖的途径存在于肾缺血再灌流所致的肺中性粒细胞浸润中。靶向HMGB1-TLR4通路可能有助于开发一种新的治疗策略，以改善急性肺和急性肾损伤的重症患者的预后。
Acute lung injury and acute kidney injury are severe complications in critically ill patients and synergistically increase mortality in intensive care units. Organ cross-talk between the kidney and the lung has been implicated recently as amplifying injury in each organ. Here we sought to identify a possible mechanism of acute kidney injury-induced acute lung injury using a mouse bilateral nephrectomy model. Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice were more resistant to lung injury including neutrophil infiltration, increased neutrophil elastase activity, and vascular permeability caused by bilateral nephrectomy compared with TLR4-wild-type C3H/HeN mice 6h after surgery. High-mobility group protein B1 (HMGB1) is one agonist for TLR4. Its blood concentrations were increased significantly by bilateral nephrectomy. Blockade of HMGB1 by neutralizing antibody reduced neutrophil infiltration in TLR4-wild-type C3H/HeN but not in TLR4-mutant C3H/HeJ mice. However, HMGB1 blockade in a renal ischemia reperfusion model reduced pulmonary neutrophil infiltration independent from TLR4. Thus, an enhanced HMGB1-TLR4 pathway contributes to lung injury induced by bilateral nephrectomy and the other HMGB1-dependent pathway exists in pulmonary neutrophil infiltration caused by renal ischemia reperfusion. Targeting the HMGB1-TLR4 pathway might enable development of a new therapeutic strategy to improve the outcomes of severely ill patients with both acute lung and acute kidney injury.