The Notch pathway attenuates burn-induced acute lung injury in rats by repressing reactive oxygen species
- Burns & Trauma Vol. 10, Issue 1, (2022)
- 作者机构：
1. Department of Burns and Cutaneous Surgery
2. Fourth Military Medical University
- 作者简介：
- 基金信息：
DOI：10.1093/burnst/tkac008
CLC：Published：2022，
Published Online：12 April 2022，
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Weixia Cai, Kuo Shen, Peng Ji, Yanhui Jia, Shichao Han, Wanfu Zhang, Xiaolong Hu, Xuekang Yang, Juntao Han, Dahai Hu, The Notch pathway attenuates burn-induced acute lung injury in rats by repressing reactive oxygen species, Burns & Trauma, Volume 10, 2022, tkac008, https://doi.org/10.1093/burnst/tkac008
Weixia Cai, Kuo Shen, Peng Ji, Yanhui Jia, Shichao Han, Wanfu Zhang, Xiaolong Hu, Xuekang Yang, Juntao Han, Dahai Hu, The Notch pathway attenuates burn-induced acute lung injury in rats by repressing reactive oxygen species, Burns & Trauma, Volume 10, 2022, tkac008, https://doi.org/10.1093/burnst/tkac008 DOI：
摘要
Abstract
BackgroundAcute lung injury (ALI) is a common complication following severe burns. The underlying mechanisms of ALI are incompletely understood; thus
available treatments are not sufficient to repair the lung tissue after ALI.MethodsTo investigate the relationship between the Notch pathway and burn-induced lung injury
we established a rat burn injury model by scalding and verified lung injury via lung injury evaluations
including hematoxylin and eosin (H&E) staining
lung injury scoring
bronchoalveolar lavage fluid and wet/dry ratio analyses
myeloperoxidase immunohistochemical staining and reactive oxygen species (ROS) accumulation analysis. To explore whether burn injury affects Notch1 expression
we detected the expression of Notch1 and Hes1 after burn injury. Then
we extracted pulmonary microvascular endothelial cells (PMVECs) and conducted Notch pathway inhibition and activation experiments
via a γ-secretase inhibitor (GSI) and OP9-DLL1 coculture
respectively
to verify the regulatory effect of the Notch pathway on ROS accumulation and apoptosis in burn-serum-stimulated PMVECs. To investigate the regulatory effect of the Notch pathway on ROS accumulation
we detected the expression of oxidative-stress-related molecules such as superoxide dismutase
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 2
NOX4 and cleaved caspase-3. NOX4-specific small interfering RNA (siRNA) and the inhibitor GKT137831 were used to verify the regulatory effect of the Notch pathway on ROS via NOX4.ResultsWe successfully established a burn model and revealed that lung injury
excessive ROS accumulation and an inflammatory response occurred. Notch1 detection showed that the expression of Notch1 was significantly increased after burn injury. In PMVECs challenged with burn serum
ROS and cell death were elevated. Moreover
when the Notch pathway was suppressed by GSI
ROS and cell apoptosis levels were significantly increased. Conversely
these parameters were reduced when the Notch pathway was activated by OP9-DLL1. Mechanistically
the inhibition of NOX4 by siRNA and GKT137831 showed that the Notch pathway reduced ROS production and cell apoptosis by downregulating the expression of NOX4 in PMVECs.ConclusionsThe Notch pathway reduced ROS production and apoptosis by downregulating the expression of NOX4 in burn-stimulated PMVECs. The Notch–NOX4 pathway may be a novel therapeutic target to treat burn-induced ALI.
关键词
Keywords
Acute lung injuryNotch pathwayReactive oxygen speciesPulmonary microvascular endothelial cellsNicotinamide adenine dinucleotide phosphate oxidase 4Burn
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