Role of lung mechanoreceptors during ventilation induced brain injury

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The development of cognitive and neuropsychological disorders in patients admitted in intensive care units have become more apparent as progress in medicine has reduced mortality rates and survivors face the repercussions of the received treatments. Supportive therapy of the failing lung requires the use of mechanical ventilation. In spite of being a life-saving technique, its use is associated to high mortality rates and severe brain alterations. By adding mechanical stress within the lung tissue, high pressures or large volumes exerted during mechanical ventilation cause a complex response of the lung parenchyma that includes activation of the inflammatory response and abnormal vagal nerve stimulation. These phenomena appear to be regulated by a mechanotransduction signaling system that leads to the development of a dopamine-related neurobehavioural disorders. Lung-brain crosstalk related disorders are a relatively recent discovered area of research in both, experimental and clinical settings, its possibilities could open promising new perspectives on the treatment of neurobehavioral disorders. Since there are only very limited treatments available for neurocognitive disorders associated with mechanical ventilation, developing novel intervention strategies therefore constitutes an urgent unmet medical need. The major research questions that will be addressed during the funding period are i) to determine whether targeting lung stretch mechanoreceptors can prevent ventilator induced brain injury (VIBI) caused by lung overdistension and ii) to assess the role of the neurotrophic factor Neuregulin-1 (NRG-1) as a possible hiperdopaminergic positive feedback during mechanical ventilation. The use of next generation MR techniques that provide fingerprinting and maximal coverage of CNS will serve us to measure mechanical ventilation related vagal activity in vivo. ) The role of the different mechanoreceptors present in the lung (TRPV1, PIEZO, TRPV4 and P2X) will be determined by using loss of function models as well as the feasibility of lidocaine administration as possible treatment.