Department of Biochemistry and Molecular Biology, State Key Laboratory of Trauma, Burn, and Combined Injury, Third Military Medical University, Chongqing 400042, China.
J Exp Med. 2013 Apr 8;210(4):839-51. doi: 10.1084/jem.20122196. Epub 2013 Mar 11.
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.
骨髓来源细胞（BMDC）相关的炎症反应在急性肺损伤（ALI）的发生发展中起着关键作用。腺苷 A2A 受体（A2AR）的激活通常被认为具有抗炎作用，可抑制 BMDC 的活性，从而起到预防 ALI 的作用。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 的 A2AR 发挥了促炎作用，加重了肺部损伤。这与在油酸诱导的 ALI 小鼠模型（非神经源性 ALI 模型）中观察到的抗炎作用形成了鲜明对比。此外，A2AR 激动剂 CGS21680 加重，而拮抗剂 ZM241385 减轻，严重 TBI 诱导的小鼠肺部炎症损伤。对来自患者或 TBI 模型小鼠的白细胞以及培养的人或鼠中性粒细胞的进一步研究表明，严重 TBI 后血浆谷氨酸水平升高，导致 A2AR 与代谢型谷氨酸受体 5（mGluR5）相互作用，增加磷脂酶 C-蛋白激酶 C 信号通路，介导 A2AR 的促炎作用。这些结果与 A2AR 在非神经源性 ALI 中众所周知的抗炎和保护作用形成鲜明对比，表明在针对 A2AR 治疗非神经源性和神经源性 ALI 时，应采用不同的治疗策略。
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