结果：与对照组相比，24h周期性牵张组肺泡上皮细胞凋亡率（45±4% vs. 6±1%，P<0.0001）及DAPK1的相对表达明显增高，DAPK1基因敲除后凋亡率降低（27±5% vs. 53±8%；P<0.0001）。在没有拉伸的情况下，观察到DAPK1过度表达促进的凋亡百分比（49±6% vs. 14±3%；P<0.0001）。B细胞淋巴瘤2（BCL2）和B细胞淋巴瘤2相关X(BCL2X)的改变与DAPK1的表达有关。与低潮气量组相比，高潮气量组小鼠肺组织中DAPK1表达和肺泡上皮细胞凋亡率较高（43±6% vs. 4±2%；P<0.0001）。通过腺相关病毒转染或DAPK1抑制剂治疗抑制DAPK1似乎可以保护肺损伤，降低肺损伤评分，缓解肺部炎症，抑制肺泡上皮细胞凋亡率（47±4%和48±6%；35±5%和34±4%；P<0.0001）。
Death-associated Protein Kinase 1 Mediates Ventilator-induced Lung Injury in Mice by Promoting Alveolar Epithelial Cell Apoptosis
Background: Alveolar epithelial cell apoptosis is implicated in the onset of ventilator-induced lung injury. Death-associated protein kinase 1 (DAPK1) is associated with cell apoptosis. The hypothesis was that DAPK1 participates in ventilator-induced lung injury through promoting alveolar epithelial cell apoptosis.
Methods: Apoptosis of mouse alveolar epithelial cell was induced by cyclic stretch. DAPK1 expression was altered (knockdown or overexpressed) in vitro by using a small interfering RNA or a plasmid, respectively. C57/BL6 male mice (n = 6) received high tidal volume ventilation to establish a lung injury model. Adeno-associated virus transfection of short hairpin RNA and DAPK1 inhibitor repressed DAPK1 expression and activation in lungs, respectively. The primary outcomes were alveolar epithelial cell apoptosis and lung injury.
Results: Compared with the control group, the 24-h cyclic stretch group showed significantly higher alveolar epithelial cell apoptotic percentage (45 ± 4% fold vs. 6 ± 1% fold; P < 0.0001) and relative DAPK1 expression, and this group also demonstrated a reduced apoptotic percentage after DAPK1 knockdown (27 ± 5% fold vs. 53 ± 8% fold; P < 0.0001). A promoted apoptotic percentage in DAPK1 overexpression was observed without stretching (49 ± 6% fold vs. 14 ± 3% fold; P < 0.0001). Alterations in B-cell lymphoma 2 and B-cell lymphoma 2-associated X are associated with DAPK1 expression. The mice subjected to high tidal volume had higher DAPK1 expression and alveolar epithelial cell apoptotic percentage in lungs compared with the low tidal volume group (43 ± 6% fold vs. 4 ± 2% fold; P < 0.0001). Inhibition of DAPK1 through adeno-associated virus infection or DAPK1 inhibitor treatment appeared to be protective against lung injury with reduced lung injury score, resolved pulmonary inflammation, and repressed alveolar epithelial cell apoptotic percentage (47 ± 4% fold and 48 ± 6% fold; 35 ± 5% fold and 34 ± 4% fold; P < 0.0001, respectively).
Conclusions: DAPK1 promotes the onset of ventilator-induced lung injury by triggering alveolar epithelial cell apoptosis through intrinsic apoptosis pathway in mice.
Wang Y, Yang Y, Chen L, et al. Death-associated Protein Kinase 1 Mediates Ventilator-induced Lung Injury in Mice by Promoting Alveolar Epithelial Cell Apoptosis. Anesthesiology. 2020;133(4):905-918. doi:10.1097/ALN.0000000000003464
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