Reduction in Blood Glutamate Levels Combined with the Genetic Inactivation of A2AR Significantly Alleviate Traumatic Brain Injury-Induced Acute Lung Injury.

Traumatic brain injury-induced acute lung injury (TBI-ALI) is a serious complication of traumatic brain injury (TBI). Our previous clinical study found that high levels of blood glutamate after TBI were closely related to the occurrence and severity of TBI-ALI, while it remains unknown whether a high concentration of blood glutamate directly causes or aggravates TBI-ALI. We found that inhibition of the adenosine A(2A) receptor (A(2A)R) after brain injury alleviated the TBI-ALI; however, it is unknown whether lowering blood glutamate levels in combination with inhibiting the A(2A)R would lead to better effects. Using mouse models of moderate and severe TBI, we found that intravenous administration of L-glutamate greatly increased the lung water content, lung-body index, level of inflammatory markers in bronchoalveolar lavage fluid and acute lung injury score and significantly decreased the PaO2/FiO(2) ratio. Moreover, the incidence of TBI-ALI and the mortality rate were significantly increased, and the combined administration of A(2A)R activator and exogenous glutamate further exacerbated the above damaging effects. Conversely, lowering the blood glutamate level through peritoneal dialysis or intravenous administration of oxaloacetate notably improved the above parameters, and a further improvement was seen with concurrent A(2A)R genetic inactivation. These data suggest that A(2A)R activation aggravates the damaging effect of high blood glutamate concentrations on the lung and that combined treatment targeting both A(2A)R and blood glutamate may be an effective way to prevent and treat TBI-ALI.