Newly Published
Critical Care Medicine  |   July 2020
Death-associated Protein Kinase 1 Mediates Ventilator-induced Lung Injury in Mice by Promoting Alveolar Epithelial Cell Apoptosis
Author Notes
  • From the Departments of Critical Care Medicine (Y.W., W.X., T.Z., S. Yuan, Y.S.) and Anesthesiology (Y.Y., L.C., L.S., B.L., S. Yao) and the Institute of Anesthesiology and Critical Care Medicine (Y.W., Y.Y., L.C., W.X., L.S., B.L., T.Z., S. Yuan, S. Yao, Y.S.), Union Hospital, Tongji Medical College and the Department of Neurobiology, School of Basic Medicine Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China (L.P.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication December 28, 2018. Accepted for publication June 16, 2020.
    Submitted for publication December 28, 2018. Accepted for publication June 16, 2020.×
  • Correspondence: Address correspondence to Dr. Shang: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Ave, Wuhan, 430022, Hubei, China. you_shang@yahoo.com. Anesthesiology’s articles are made freely accessible to all readers on www.anesthesiology.org, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Critical Care / Respiratory System
Critical Care Medicine   |   July 2020
Death-associated Protein Kinase 1 Mediates Ventilator-induced Lung Injury in Mice by Promoting Alveolar Epithelial Cell Apoptosis
Anesthesiology Newly Published on July 23, 2020. doi:https://doi.org/10.1097/ALN.0000000000003464
Anesthesiology Newly Published on July 23, 2020. doi:https://doi.org/10.1097/ALN.0000000000003464
Abstract

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.

Editor’s Perspective:

What We Already Know about This Topic:

  • Ventilator-related lung injury may be related to stretch-induced apoptosis

  • DAPK1 is involved in various apoptotic signal transduction pathways

  • The role of DAPK1 in ventilator-related lung injury is not well understood

What This Article Tells Us That Is New:

  • In mice, high tidal volumes increased cyclic stretch, DAPK1 expression, and epithelial cell apoptosis

  • Inhibition of DAPK1 appeared to be protective against lung injury, reducing lung injury, inflammation, and apoptosis

  • DAPK1 triggers alveolar epithelial cell apoptosis and mediates ventilator-induced lung injury in mice