Plasma glutamate-modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain injury-induced acute lung injury.
Plasma glutamate-modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain injury-induced acute lung injury.
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DOI：
10.1084/jem.20122196
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发表时间：
2013-04-08
期刊：
影响因子：
--
通讯作者：
Zhou YG
中科院分区：
文献类型：
--
作者：
Dai SS;Wang H;Yang N;An JH;Li W;Ning YL;Zhu PF;Chen JF;Zhou YG
腺苷 A2A 受体的激活会加重神经源性急性肺损伤 (ALI) 小鼠模型的肺损伤，但可以预防非神经源性 ALI。骨髓源性细胞（BMDC）相关的炎症反应在急性肺损伤（ALI）的发生过程中发挥着关键作用。腺苷 A2A 受体 (A2AR) 的激活通常被认为具有抗炎作用，通过抑制 BMDC 活性来预防 ALI。然而，在本研究中，我们发现在严重创伤性脑损伤（TBI）诱导的神经源性ALI小鼠模型中，BMDC A2AR发挥促炎作用，加重肺损伤。这与小鼠油酸诱导的 ALI 模型（非神经源性 ALI 模型）中观察到的抗炎作用形成鲜明对比。此外，A2AR 激动剂 CGS21680 加重了小鼠中 TBI 诱导的严重肺部炎症损伤，而拮抗剂 ZM241385 则减弱。对从患者或小鼠 TBI 模型中分离的白细胞以及培养的人或小鼠中性粒细胞的进一步研究表明，严重 TBI 后血浆谷氨酸升高诱导 A2AR 与代谢型谷氨酸受体 5 (mGluR5) 之间的相互作用，增加磷脂酶 C-蛋白激酶 C 信号传导，从而介导 A2AR 的促炎作用。这些结果与众所周知的 A2AR 在非神经源性 ALI 中的抗炎和保护作用形成鲜明对比，并表明在靶向 A2AR 时，应采用不同的治疗策略来治疗非神经源性和神经源性 ALI。
Activation of adenosine A2A receptor aggravates lung damage in a neurogenic mouse model of acute lung injury (ALI) but protects against nonneurogenic ALI. The bone marrow–derived cell (BMDC)–associated inflammatory response plays a key role in the development of acute lung injury (ALI). Activation of adenosine A2A receptor (A2AR) is generally considered to be antiinflammatory, inhibiting BMDC activities to protect against ALI. However, in the present study, we found that in a mouse model of neurogenic ALI induced by severe traumatic brain injury (TBI), BMDC A2AR exerted a proinflammatory effect, aggravating lung damage. This is in contrast to the antiinflammatory effect observed in the mouse oleic acid–induced ALI model (a nonneurogenic ALI model.) Moreover, the A2AR agonist CGS21680 aggravated, whereas the antagonist ZM241385 attenuated, the severe TBI-induced lung inflammatory damage in mice. Further investigation of white blood cells isolated from patients or mouse TBI models and of cultured human or mouse neutrophils demonstrated that elevated plasma glutamate after severe TBI induced interaction between A2AR and the metabotropic glutamate receptor 5 (mGluR5) to increase phospholipase C–protein kinase C signaling, which mediated the proinflammatory effect of A2AR. These results are in striking contrast to the well-known antiinflammatory and protective role of A2AR in nonneurogenic ALI and indicate different therapeutic strategies should be used for nonneurogenic and neurogenic ALI treatment when targeting A2AR.
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影响因子：
5.8
作者：
Chung, Liping;Nelson, Anne E.;Baxter, Robert C.
通讯作者：
Baxter, Robert C.
DOI：
10.1073/pnas.172393799
发表时间：
2002-09-03
影响因子：
11.1
作者：
Ferré, S;Karcz-Kubicha, M;Ciruela, F
通讯作者：
Ciruela, F
影响因子：
6.7
作者：
Fredholm, Bertil B.;Chern, Yijuang;Sitkovsky, Michail
通讯作者：
Sitkovsky, Michail
影响因子：
8.8
作者：
Abraham, E
通讯作者：
Abraham, E
DOI：
10.1164/ajrccm.154.1.8680703
发表时间：
1996-07-01
影响因子：
24.7
作者：
Baughman, RP;Gunther, KL;Pattishall, EN
通讯作者：
Pattishall, EN