Adrián González-López, Inés López-Alonso, Alina Aguirre, Laura Amado-Rodríguez, Estefanía Batalla-Solís, Aurora Astudillo, Cristina Tomás-Zapico, Antonio Fueyo, Claudia C. dos Santos, Konrad Talbot, and Guillermo M. Albaiceta Am. J. Resp. Crit. Care Med. Sep 15, 2013, vol. 188, no. 6: 693-702
Abstract
Rationale: Critically ill patients frequently develop neuropsychological disturbances including acute delirium or memory impairment. The need for mechanical ventilation is a risk factor for these adverse events, but a mechanism that links lung stretch and brain injury has not been identified.
Objectives: To identify the mechanisms that lead to brain dysfunction during mechanical ventilation.
Methods: Brains from mechanically ventilated mice were harvested, and signals of apoptosis and alterations in the Akt survival pathway were studied. These measurements were repeated in vagotomized or haloperidol-treated mice, and in animals intracerebroventricularly injected with selective dopamine-receptor blockers. Hippocampal slices were cultured and treated with micromolar concentrations of dopamine, with or without dopamine receptor blockers. Last, levels of dysbindin, a regulator of the membrane availability of dopamine receptors, were assessed in the experimental model and in brain samples from ventilated patients.
Measurements and Main Results: Mechanical ventilation triggers hippocampal apoptosis as a result of type 2 dopamine receptor activation in response to vagal signaling. Activation of these receptors blocks the Akt/GSK3β prosurvival pathway and activates the apoptotic cascade, as demonstrated in vivo and in vitro. Vagotomy, systemic haloperidol, or intracerebroventricular raclopride (a type 2 dopamine receptor blocker) ameliorated this effect. Moreover, ventilation induced a concomitant change in the expression of dysbindin-1C. These results were confirmed in brain samples from ventilated patients.
Conclusions: These results prove the existence of a pathogenic mechanism of lung stretch–induced hippocampal apoptosis that could explain the neurological changes in ventilated patients and may help to identify novel therapeutic approaches.
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