Regulation of lung injury and repair by Toll-like receptors and hyaluronan
Regulation of lung injury and repair by Toll-like receptors and hyaluronan
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DOI：
10.1038/nm1315
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发表时间：
2005-11-01
期刊：
影响因子：
82.9
通讯作者：
Noble, PW
中科院分区：
文献类型：
--
作者：
Jiang, DH;Liang, JR;Noble, PW
急性肺损伤后调节炎症和修复的机制尚不完全清楚。细胞外基质糖胺聚糖透明质酸是在组织损伤后产生的，并且受损的清除导致持续的炎症。在这里，我们报告透明质酸降解产物需要MyD 88和Toll样受体（TLR）4和TLR 2在体外和体内启动急性肺损伤的炎症反应。从急性肺损伤患者血清中分离的海洛宁片段以TLR 4和TLR 2依赖的方式刺激巨噬细胞趋化因子的产生。Myd 88（-/-）和Tlr 4（-/-）Tlr 2（-/-）小鼠在肺损伤后表现出炎性细胞跨上皮迁移受损，但存活率降低，上皮细胞凋亡增加。肺上皮细胞特异性高分子量透明质酸过表达对急性肺损伤具有保护作用。此外，上皮细胞表面透明质酸对细胞凋亡具有保护作用，部分是通过TLR依赖的NF-κ B的基础激活。透明质酸-TLR 2和透明质酸-TLR 4相互作用提供启动炎症反应、维持上皮细胞完整性和促进急性肺损伤恢复的信号。
Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor ( TLR) 4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappa B. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.