Role of lung mechanoreceptors during ventilation induced brain injury

随着医学的进步降低了死亡率，幸存者面临着接受治疗的影响，重症监护病房患者的认知和神经心理障碍的发展变得更加明显。对衰竭的肺进行支持性治疗需要使用机械通风。尽管它是一种拯救生命的技术，但它的使用与高死亡率和严重的大脑变化有关。通过在肺组织内增加机械应力，在机械通气过程中施加的高压或大容量会引起肺实质的复杂反应，包括激活炎症反应和异常迷走神经刺激。这些现象似乎受到一种机械转导信号系统的调节，该系统导致与多巴胺相关的神经行为障碍的发展。肺-脑串音相关障碍是一个相对较新的研究领域，无论是在实验还是临床环境下，它的可能性都可能为神经行为障碍的治疗开辟新的前景。由于与机械通气相关的神经认知障碍的治疗方法非常有限，因此开发新的干预策略构成了一个迫切的未得到满足的医疗需求。在资助期间将解决的主要研究问题是：i)确定靶向肺拉伸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)；ii)评估神经营养因子神经调节蛋白-1(NRG-1)在机械通气过程中作为可能的高多巴胺能正反馈的作用。下一代磁共振技术的使用将提供中枢神经系统的指纹和最大覆盖范围，这将有助于我们在活体内测量与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(TRPV1、PARZO、TRPV4和P2X)的作用将通过功能丧失模型以及利多卡因作为可能的治疗方法的可行性来确定。

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.