A protective Hsp70-TLR4 pathway in lethal oxidant lung injury.
A protective Hsp70-TLR4 pathway in lethal oxidant lung injury.
复制标题
DOI：
10.4049/jimmunol.1300052
复制
发表时间：
2013-08-01
期刊：
影响因子：
--
通讯作者：
Lee PJ
中科院分区：
文献类型：
--
作者：
Zhang Y;Zhang X;Shan P;Hunt CR;Pandita TK;Lee PJ
给予高水平的吸入氧或高氧通常被用作危重患者的生命维持措施。然而，长时间接触会加剧呼吸衰竭。我们之前的研究表明，Toll 样受体 4 (TLR4) 可以预防高氧引起的肺损伤和死亡。 Hsp70 具有有效的细胞保护特性，并被描述为细胞系中的 TLR4 配体。我们试图在体外和体内阐明 TLR4 和 Hsp70 在高氧诱导的肺损伤中的关系，并确定所涉及的信号传导机制。野生型、TLR4−/− 和 Trif−/−（TLR4 接头蛋白）鼠肺内皮细胞 (MLEC) 暴露于高氧环境。我们发现高氧后小鼠肺和 MLEC 的细胞内和分泌的 Hsp70 水平显着升高。我们证实 Hsp70 和 TLR4 在肺组织和 MLEC 中共免疫沉淀。 Hsp70 介导的 NFκB 激活似乎依赖于 TLR4。当 TLR4 缺失时，Hsp70 在内皮细胞中失去保护作用。此外，Hsp70 的这些保护特性依赖于 TLR4 接头 Trif，而不依赖于 MyD88。 Hsp70 缺陷型小鼠在高氧条件下死亡率增加，Hsp70 的肺靶向腺病毒递送有效地拯救了 Hsp70 缺陷型小鼠和野生型小鼠。我们的研究首次定义了肺和内皮细胞中的 Hsp70-TLR4-Trif 细胞保护轴。该途径是针对一系列氧化剂引起的肺损伤的潜在治疗靶点。
Administering high levels of inspired oxygen, or hyperoxia, is commonly used as a life-sustaining measure in critically ill patients. However, prolonged exposures can exacerbate respiratory failure. Our previous study showed that toll-like receptor 4 (TLR4) confers protection against hyperoxia-induced lung injury and mortality. Hsp70 has potent cytoprotective properties and has been described as a TLR4 ligand in cell lines. We sought to elucidate the relationship between TLR4 and Hsp70 in hyperoxia-induced lung injury in vitro and in vivo and to define the signaling mechanisms involved. Wild type, TLR4−/− and Trif−/− (a TLR4 adapter protein) murine lung endothelial cells (MLEC) were exposed to hyperoxia. We found markedly elevated levels of intracellular and secreted Hsp70 from mice lung and MLEC after hyperoxia. We confirmed that Hsp70 and TLR4 co-immunoprecipitate in lung tissue and MLEC. Hsp70-mediated NFκB activation appears to depend upon TLR4. In the absence of TLR4, Hsp70 loses its protective effects in endothelial cells. Furthermore, these protective properties of Hsp70 are TLR4 adapter Trif-dependent, MyD88-independent. Hsp70-deficient mice have increased mortality during hyperoxia and lung-targeted adenoviral delivery of Hsp70 effectively rescues both Hsp70-deficient and wild type mice. Our studies are the first to define an Hsp70-TLR4-Trif cytoprotective axis in the lung and endothelial cells. This pathway is a potential therapeutic target against a range of oxidant-induced lung injuries.
登录
查看更多内容
影响因子：
8.8
作者：
Goss, CH;Brower, RG;Rubenfeld, GD
通讯作者：
Rubenfeld, GD
影响因子：
4.4
作者：
Jeyaseelan, Samithamby;Young, Scott K.;Worthen, G. Scott
通讯作者：
Worthen, G. Scott
影响因子：
4.4
作者：
Enomoto, Yutaka;Bharti, Ajit;Gong, Jianlin
通讯作者：
Gong, Jianlin
影响因子：
4.4
作者：
Fan, Jie;Li, Yuehua;Wilson, Mark A.
通讯作者：
Wilson, Mark A.
影响因子：
4.8
作者：
Asea, A;Rehli, M;Calderwood, SK
通讯作者：
Calderwood, SK