TOLL-LIKE RECEPTOR 4 REGULATES HEME OXYGENASE-1 EXPRESSION AFTER HEMORRHAGIC SHOCK INDUCED ACUTE LUNG INJURY IN MICE: REQUIREMENT OF P38 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION
TOLL-LIKE RECEPTOR 4 REGULATES HEME OXYGENASE-1 EXPRESSION AFTER HEMORRHAGIC SHOCK INDUCED ACUTE LUNG INJURY IN MICE: REQUIREMENT OF P38 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION
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DOI：
10.1097/shk.0b013e318188f7e1
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发表时间：
2009-05-01
期刊：
影响因子：
3.1
通讯作者：
Peng, Mian
中科院分区：
文献类型：
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作者：
Chen, Chang;Wang, Yanlin;Peng, Mian
急性肺损伤（acute lung injury，ALI）是休克或创伤后常见的并发症之一. Toll样受体（TLR）在感染和无菌损伤的情况下通过响应各种微生物和内源性配体而处于先天免疫激活的界面。本研究旨在探讨TLR-4在肺损伤诱导的急性肺损伤中的作用，并探讨其在非感染性急性肺损伤中的信号转导途径和机制。小鼠经历失血性休克和复苏（HSR）。动脉血气;分别于HSR后6、24和48 h检测TLR-4、血红素加氧酶1（HO-1）和p38丝裂原活化蛋白激酶（p38 MAPK）的表达、髓过氧化物酶活性、肺湿/干比和肺组织中IL-10水平。失血性休克和复苏诱导C3 H/HeN小鼠TLR-4、HO-1和p38 MAPK表达显著增加。HSR后24 h，IL-10和髓过氧化物酶明显升高，C3 H/HeN小鼠出现Pao（2）/吸氧分数低于300 mmHg的ALI。与C3 H/HeJ小鼠相比，C3 H/HeN小鼠各细胞因子水平的诱导量及TLR-4、HO-1和p38 MAPK的表达均显著增加。本研究表明，肺p38 MAPK在HSR后被激活，p38 MAPK抑制剂FR 167653抑制ALI后HO-1的诱导。结论TLR-4可诱导HO-1 mRNA的表达，可能参与了p38 MAPK的激活，从而导致HSR后肺功能障碍的发生。
Acute lung injury (ALI) leading to respiratory distress is a common sequela of shock or trauma. The toll-like receptors (TLRs) stand at the interface of innate immune activation in the settings of both infection and sterile injury by responding to a variety of microbial and endogenous ligands alike. This work explored the effects of TLR-4 on hemorrhage-induced ALI and characterizes the signaling pathways and the mechanisms involved in noninfectious ALI. Mice underwent hemorrhagic shock and resuscitation (HSR). Arterial blood gases; expressions of TLR-4, heme oxygenase 1 (HO-1), and p38 mitogen-activated protein kinase (p38MAPK); myeloperoxidase activity; lung wet/dry ratios; and IL-10 levels in lung tissues were obtained at 6, 24, and 48 h after HSR. Hemorrhagic shock and resuscitation induced significant expressions of TLR-4, HO-1, and p38MAPK in C3H/HeN mice. IL-10 and myeloperoxidase were markedly increased at 24 h after HSR, and C3H/HeN mice had ALI with Pao(2)/fraction of inspired oxygen less than 300 mmHg. The induced amount of each cytokine level and the expressions of TLR-4, HO-1, and p38MAPK of C3H/HeN mice were significantly higher compared with C3H/HeJ mice. This study demonstrated that lung p38MAPK is activated after HSR, and p38MAPK inhibitor FR167653 suppresses HO-1 induction after ALI. We concluded that TLR-4 might induce HO-1 messenger RNA expression, which is probably involved in p38MAPK activation in the development of the lung dysfunction after HSR.