Lung Purinoceptor Activation Triggers Ventilator-Induced Brain Injury

Abstract

Objectives:Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury.Design:Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies.Setting:Research laboratory.Subjects:Wild-type, TRPV4-deficient C57BL/6J mice, 8–10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B.Intervention:Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients.Measurements and Main Results:Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4–/– mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilatedConclusions:TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury.

Systematic review of cognitive impairment and brain insult after mechanical ventilation

“…Although these studies were not able to entirely control for factors that co-varied with MV, such as sedation or immobility, there is a consistent signal across all studies showing an association between MV and brain insult. High levels of pro-apoptotic proteins and elevated levels of inflammatory cells in the brain after MV were reported in nine preclinical papers identified in our systematic review (see Table 1 ) [ 3 , 5 , 6 , 13 – 18 ].…”

“…Two preclinical papers investigated the neural pathway for brain insult after MV [ 3 , 18 ]. It has been proposed that the neural signal coming from the vagus nerve triggers neuroinflammation and brain injury during MV [ 3 ].…”

“…It has been proposed that the neural signal coming from the vagus nerve triggers neuroinflammation and brain injury during MV [ 3 ]. In the postulated neural pathway for VIBI, the vagal afferent signal changes as a result of cyclical alveolar stretch due to positive-pressure MV, leading to activation of pulmonary transient receptor potential vanilloid channel type 4 (TRPV4), and consequently to a reduction in gene expression of pulmonary TRPV4 and purinergic type 2X receptors [ 18 ]. According to the authors, the pulmonary TRPV4 activation would lead to a hippocampal overexpression of type 2 dopamine receptors, which would deactivate the B/glycogen synthetase kinase 3β (Akt/GSK3β), initiating the apoptotic cascade [ 18 ].…”

“…In the postulated neural pathway for VIBI, the vagal afferent signal changes as a result of cyclical alveolar stretch due to positive-pressure MV, leading to activation of pulmonary transient receptor potential vanilloid channel type 4 (TRPV4), and consequently to a reduction in gene expression of pulmonary TRPV4 and purinergic type 2X receptors [ 18 ]. According to the authors, the pulmonary TRPV4 activation would lead to a hippocampal overexpression of type 2 dopamine receptors, which would deactivate the B/glycogen synthetase kinase 3β (Akt/GSK3β), initiating the apoptotic cascade [ 18 ]. In order to demonstrate the hypothesized neural signaling pathway for VIBI, researchers compared hippocampal apoptosis in mechanically ventilated subjects with chemical vagotomy, with surgical vagotomy, and without vagotomy, and in never-ventilated subjects [ 3 , 18 ].…”

“…According to the authors, the pulmonary TRPV4 activation would lead to a hippocampal overexpression of type 2 dopamine receptors, which would deactivate the B/glycogen synthetase kinase 3β (Akt/GSK3β), initiating the apoptotic cascade [ 18 ]. In order to demonstrate the hypothesized neural signaling pathway for VIBI, researchers compared hippocampal apoptosis in mechanically ventilated subjects with chemical vagotomy, with surgical vagotomy, and without vagotomy, and in never-ventilated subjects [ 3 , 18 ]. It was found that vagotomy, either chemical or surgical, mitigated ventilation-induced brain injury [ 3 ].…”