title: Plasma glutamate-modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain injury-induced acute lung injury.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Trauma, Burn, and Combined Injury, Third Military Medical University, Chongqing 400042, China.
authors.forename: Shuang-Shuang
authors.initials: SS
authors.lastname: Dai
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: An
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Ya-Lei
authors.initials: YL
authors.lastname: Ning
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Zhu
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
authors.forename: Yuan-Guo
authors.initials: YG
authors.lastname: Zhou
mesh_terms: D055371:Acute Lung Injury / Q000097:blood* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000097:blood* / Q000150:complications / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018698:Glutamic Acid / Q000097:blood* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010627:Phenethylamines / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D018698:Glutamic Acid; D011493:Protein Kinase C; D010738:Type C Phospholipases; D000241:Adenosine