Role of lung mechanoreceptors during ventilation induced brain injury

由于医学的进步降低了死亡率，而幸存者面临着所接受治疗的影响，因此，重症监护室收治的患者中认知和神经心理障碍的发展变得更加明显。衰竭肺的支持治疗需要使用机械通气。尽管它是一种挽救生命的技术，但它的使用与高死亡率和严重的大脑改变有关。通过在肺组织内增加机械应力，在机械通气期间施加的高压或大容量引起肺实质的复杂反应，包括炎症反应的激活和异常迷走神经刺激。这些现象似乎是由一个机械信号转导系统，导致多巴胺相关的神经行为障碍的发展。肺脑串扰相关疾病是一个相对较新的研究领域，在实验和临床环境中，它的可能性可能会打开有前途的新的角度治疗神经行为障碍。由于只有非常有限的治疗方法可用于与机械通气相关的神经认知障碍，因此开发新的干预策略构成了迫切的未满足的医疗需求。在资助期间将解决的主要研究问题是：i）确定靶向肺牵张机械感受器是否可以预防由肺过度扩张引起的呼吸机诱导的脑损伤（VIBI），以及ii）评估神经营养因子Neuregulin-1（NRG-1）在机械通气期间作为可能的高多巴胺能正反馈的作用。使用下一代MR技术，提供指纹和CNS的最大覆盖范围将有助于我们测量体内机械通气相关的迷走神经活动。肺中存在的不同机械感受器（TRPV 1、PIEZO、TRPV 4和P2 X）的作用将通过使用功能丧失模型以及利多卡因施用作为可能治疗的可行性来确定。

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.