多巴胺D1受体激活改善机械通气诱导肺血管屏障功能障碍的作用及其机制研究

Mechanical ventilation is an indispensible supportive therapy for patients with acute respiratory failure. However, lung overdistension induced by mechanical ventilation at high tidal volumes may also cause or aggravate lung injury, which seems to be responsible for the poor outcome observed in patients requiring prolonged mechanical ventilation. In our preliminary study, we found that mechanical ventilation downregulated dopamine D1 receptor (DRD1) expression in mouse lung tissues in a time-dependent manner. Moreover, lung tissues harvested from mechanically ventilated patients were also used to determine protein levels of DRD1 and DRD2. It was found that pulmonary DRD1 expression, but not DRD2 expression, was negatively correlated with duration of mechanical ventilation. In addition, we found that gene knockout of DRD1 significantly aggravated, whereas selective DRD1 agonist attenuated mechanical ventilation-induced acute lung injury (VILI). By using bioinformatics analysis of four microarray studies of ventilated mouse lung samples, it was found that matrix metalloproteinases (MMPs) were significantly elevated in the lung tissues of mice subjected to mechanical ventilation. We found that DRD1 agonist blocked mechanical stretch-induced MMPs expression both in vivo mechanical ventilation-induced acute lung injury (VILI) mouse models and in vitro cyclic stretch-treated pulmonary vascular endothelial cells. Both DRD1 agonist and MMPs inhibitor significantly attenuated cyclic stretch-induced pulmonary vascular endothelial injury. Taken together, these findings suggest that activation of DRD1 may alleviate mechanical stretch-induced pulmonary endothelial injury via inhibiting MMPs expression. On the basis of these results, the present proposal will firstly verify that upregulation of MMPs induced by mechanical stretch may associate with junction proteins on pulmonary vascular endothelial cells, and then modulate the downstream signaling pathways involved in endothelial injury. Whether these mechanisms play central roles in the protective effect of DRD1 activation against mechanical stretch-induced pulmonary vascular barrier dysfunction will also be investigated in the present project. The present study will provide reliable evidence to elucidate the mechanisms involved in the pathogenesis of mechanical ventilation-induced acute lung injury. Selective activation of DRD1 may become one of the future treatment options of mechanical ventilation-induced lung injury.

机械通气在提供呼吸支持治疗同时也可能导致或进一步加重肺损伤，由此增加危重患者的不良预后。通过动物模型和临床样本两方面的预实验，我们发现机械通气可以抑制肺组织多巴胺D1受体（DRD1）表达；此外，DRD1基因敲除可以加重、而DRD1激活可以减轻机械通气诱导的急性肺损伤（VILI）。通过基因芯片生物信息学分析结合动物和细胞水平的工作，我们发现DRD1激活可能通过抑制基质金属蛋白酶（MMPs）表达从而减轻机械牵拉诱导的肺血管内皮损伤。在此基础上，本项目拟证实机械牵拉诱导MMPs表达增多后，MMPs可以作用于肺血管内皮细胞上构成连接结构的膜蛋白，继而调控内皮损伤相关的信号通路，由此介导机械牵拉诱导的血管内皮损伤。我们还将证实相关机制在DRD1激活减轻机械牵拉诱导肺血管屏障功能障碍过程中的关键作用。本项目研究将有助于阐明VILI的发生机制，并从选择性多巴胺受体D1受体激活的角度为临床治疗提供新思路

机械通气在提供呼吸支持治疗同时也可能导致或进一步加重肺损伤，由此增加危重患者的不良预后。通过动物模型和临床样本两方面的预实验，我们发现机械通气可以抑制肺组织多巴胺D1受体（DRD1）表达；此外，DRD1基因敲除可以加重、而DRD1激活可以减轻机械通气诱导的急性肺损伤（VILI）。通过基因芯片生物信息学分析结合动物和细胞水平的工作，我们发现DRD1激活可能通过抑制基质金属蛋白酶（MMPs）表达从而减轻机械牵拉诱导的肺血管内皮损伤。在此基础上，本项目证实了机械牵拉诱导MMPs表达增多后，MMPs可以作用于肺血管内皮细胞上构成连接结构的膜蛋白，继而调控内皮损伤相关的信号通路，由此介导机械牵拉诱导的血管内皮损伤。我们还证实了相关机制在DRD1激活减轻机械牵拉诱导肺血管屏障功能障碍过程中的关键作用。本项目研究通过阐明VILI的发生机制，并从选择性多巴胺受体D1受体激活的角度为临床治疗提供了新思路。