TLR4 Activity Is Required in the Resolution of Pulmonary Inflammation and Fibrosis after Acute and Chronic Lung Injury
TLR4 Activity Is Required in the Resolution of Pulmonary Inflammation and Fibrosis after Acute and Chronic Lung Injury
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TLR4 活性是解决急性和慢性肺损伤后肺部炎症和纤维化所必需的
DOI：
10.1016/j.ajpath.2011.09.019
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发表时间：
2012-01-01
影响因子：
6
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
--
作者：
Yang, Hong-Zhen;Wang, Jia-Ping;Hu, Zhuo-Wei
肺纤维化是一种炎症驱动的肺部疾病，预后不良且无法治愈。在这里，我们报告说，基础toll样受体4（TLR 4）的活动是至关重要的急性和慢性炎症和肺纤维化的小鼠模型肺损伤的决议。我们发现TLR 4的遗传或药理学抑制通过促进免疫抑制组织微环境的形成和减弱纤维化肺组织中胶原蛋白的自噬相关降解和细胞死亡而加剧博莱霉素诱导的肺部炎症、纤维化、功能障碍和动物死亡。相比之下，药物激活TLR 4导致急性炎症的快速消退，逆转了已建立的肺纤维化，改善了肺功能，并将小鼠从死亡中拯救出来。类似地，阻断TLR 4会削弱二氧化硅诱导的慢性炎症和纤维化的消退。重要的是，改变自噬活性可以逆转TLR 4调节的肺部炎症、纤维化、功能障碍和动物死亡。自噬激活剂雷帕霉素逆转了TLR 4拮抗作用。相反，3-甲基腺嘌呤抑制自噬逆转了TIR 4激动剂的促分解和抗纤维化作用，并增加了动物死亡。这些结果不仅突出了TLR 4介导的基础免疫，特别是自噬活性，在化学诱导的肺损伤后炎症和纤维化的前消退中的关键作用，而且还为激活TLR 4信号传导，特别是TLR 4介导的自噬的概念提供了证据，作为针对对当前治疗无反应的慢性纤维增生性疾病的新治疗策略。(Am J Pathol 2012，180：275-292; DOI：10.1016/j.ajpath.2011.09.019）
Pulmonary fibrosis is an inflammation-driven lung disease with a poor prognosis and no cure. Here we report that basal toll-like receptor 4 (TLR4) activity is critical for the resolution of acute and chronic inflammation and pulmonary fibrosis in mouse models of lung injury. We found that genetic or pharmacologic inhibition of TLR4 exacerbates bleomycin-induced pulmonary inflammation, fibrosis, dysfunction, and animal death through promoting formation of an immunosuppressive tissue microenvironment and attenuating autophagy-associated degradation of collagen and cell death in the fibrotic lung tissues. In contrast, pharmacologic activation of TLR4 resulted in a quick resolution of acute inflammation, reversed the established pulmonary fibrosis, improved lung function, and rescued mice from death. Similarly, blocking TLR4 impaired the resolution of silica-induced chronic inflammation and fibrosis. Importantly, altering autophagic activity could reverse the TLR4-regulated lung inflammation, fibrosis, dysfunction, and animal death. Rapamycin, an autophagy activator, reversed the effects of TLR4 antagonism. In contrast, inhibition of autophagy by 3-methyladenine reversed the proresolving and antifibrotic roles of TIR4 agonists and increased animal death. These results not only highlight a pivotal role for TLR4-mediated basal immunity, particularly autophagic activity, in the proresolution of inflammation and fibrosis after chemical-induced lung injury but also provide proof for the concept for activating TLR4 signaling, particularly TLR4-mediated autophagy, as a novel therapeutic strategy against chronic fibroproliferative diseases that are unresponsive to current therapy. (Am J Pathol 2012, 180: 275-292; DOI: 10.1016/j.ajpath.2011.09.019)