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NADPH oxidase 4 signaling in a ventilator-induced lung injury mouse model

 Sang Hoon Lee  ;  Mi Hwa Shin   ;  Ah Young Leem   ;  Su Hwan Lee   ;  Kyung Soo Chung   ;  Young Sam Kim   ;  Moo Suk Park 
 RESPIRATORY RESEARCH, Vol.23(1) : 73, 2022-03 
Journal Title
Issue Date
Animals ; Humans ; Lung / metabolism ; Male ; Mice ; Mice, Inbred C57BL ; NADPH Oxidase 4* / genetics ; NADPH Oxidase 4* / metabolism ; Signal Transduction ; Ventilator-Induced Lung Injury* / metabolism
EphA2 ; IL-6 ; Lung injury ; NADPH oxidase 4 ; Ventilator
Background: For patients with acute respiratory distress syndrome, a ventilator is essential to supply oxygen to tissues, but it may also cause lung damage. In this study, we investigated the role of NOX4 using NOX4 knockout (KO) mice and NOX4 inhibitors in a ventilator-induced lung injury (VILI) model.

Methods: Wild-type (WT) male C57BL/6J mice and NOX4 knockout (KO) male mice were divided into five groups: (1) control group; (2) high tidal ventilation (HTV) group: WT mice + HTV ± DMSO; (3) NOX4 KO group; (4) NOX4 KO with HTV group; (5) NOX4 inhibitor group: WT mice + HTV + NOX4 inhibitor. In the VILI model, the supine position was maintained at 24 mL/kg volume, 0 cm H2O PEEP, 100/min respiratory rate, and 0.21 inspired oxygen fraction. In the NOX4 inhibitor group, 50 μL anti-GKT 137831 inhibitor was injected intraperitoneally, 2 h after ventilator use. After 5 h of HTV, mice in the ventilator group were euthanized, and their lung tissues were obtained for further analysis. In addition, the relationship between EphA2 (which is related to lung injury) and NOX4 was investigated using EphA2 KO mice, and NOX4 and EphA2 levels in the bronchoalveolar lavage fluid (BALF) of 38 patients with pneumonia were examined.

Results: Cell counts from BALFs were significantly lower in the NOX4 KO with HTV group (p < 0.01) and EphA2 KO with HTV group (p < 0.001) compared to that in the HTV group. In the NOX4 inhibitor group, cell counts and protein concentrations from BALF were significantly lower than those in the HTV group (both, p < 0.001). In the NOX4 KO group and the NOX4 inhibitor group, EphA2 levels were significantly lower than those in the HTV group (p < 0.001). In patients with respiratory disease, NOX4 and EphA2 levels were significantly higher in patients with pneumonia and patients who received ventilator treatment in the intensive care unit.

Conclusion: In the VILI model with high tidal volume, NOX4 KO, EphA2 KO or monoclonal antibodies attenuated the VILI. NOX4 and EphA2 levels were significantly higher in patients with pneumonia and especially in mechanical ventilated in the ICU. Inhibition of Nox4 is a potential therapeutic target for the prevention and reduction of VILI.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Young Sam(김영삼) ORCID logo https://orcid.org/0000-0001-9656-8482
Park, Moo Suk(박무석) ORCID logo https://orcid.org/0000-0003-0820-7615
Lee, Sang Hoon(이상훈) ORCID logo https://orcid.org/0000-0002-7706-5318
Lee, Su Hwan(이수환) ORCID logo https://orcid.org/0000-0002-3487-2574
Leem, Ah Young(임아영) ORCID logo https://orcid.org/0000-0001-5165-3704
Jung, Kyung Soo(정경수) ORCID logo https://orcid.org/0000-0003-1604-8730
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