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Dihydromyricetin Alleviates Sepsis-Induced Acute Lung Injury through Inhibiting NLRP3 Inflammasome-Dependent Pyroptosis in Mice Model

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Abstract

Increasing evidence demonstrates that pyroptosis, pro-inflammatory programmed cell death, is linked to acute lung injury (ALI). Dihydromyricetin (DHM) has been reported to exert anti-inflammatory effects by inhibiting NLRP3 inflammasome activation in vascular endothelial cells. However, the effects of DHM on NLRP3 inflammasome-induced pyroptosis in ALI remain elusive. In the present study, male BALB/c mice were subjected to cecal ligation and puncture (CLP), and DHM (50, 100, 150 mg/kg) was orally administered (once per day, for 3 days) 2 h after CLP. After 72 h, lung histopathology was examined, and the wet/dry (W/D) ratio, inflammatory infiltration, total protein concentration, total cell, and neutrophil counts were detected. Myeloperoxidase (MPO), interleukin (IL)-6, TNF-α, IL-1β, and IL-18 levels in bronchoalveolar lavage fluid (BALF) were measured by ELISA. Additionally, the expression of NLRP3 signaling pathway proteins were detected by Western blotting. The results revealed that in BALF, DHM (150 mg/kg) treatment significantly reduced the CLP-induced lung histopathological injury, inflammatory cell infiltration, total cell and neutrophil number, and total protein and albumin concentration. DHM treatment significantly inhibited the CLP-induced NLRP3 inflammasome pathway (NLRP3, ASC, caspase-1, gasdermin D (Gsdmd), IL-1β, and IL-18). In conclusion, these results demonstrate that DHM protects against CLP-induced ALI by inhibiting NLRP3 inflammasome activation and subsequent pyroptosis.

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Abbreviations

DHM:

Dihydromyricetin

NLRP3:

NLR pyrin domain containing 3

ASC:

Apoptosis-associated speck-like protein containing CARD

ALI:

Acute lung injury

CLP:

Cecal ligation and puncture

W/D:

Wet/dry

MPO:

Myeloperoxidase

IL:

Interleukin

BALF:

Bronchoalveolar lavage fluid

Gsdmd:

Gasdermin D

SIRS:

Systemic inflammatory response syndrome

MODS:

Multiple organ dysfunction syndrome

ARDS:

Acute respiratory distress syndrome

CMC-Na:

Carboxymethylcellulose

H&E:

Hematoxylin and eosin

DAPI:

4′,6-Diamidino-2-phenylindole

PVDF:

Polyvinylidene fluoride

SEM:

Standard error of the mean

ANOVA:

Analysis of variance

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Acknowledgements

Zhan-fei Li is currently receiving grants from National Natural Science Foundation of China (No. 81571891) and Technology Research Plan of Wuhan (No. 2015060101010035). Xiang-jun Bai is currently receiving grants from National Natural Science Foundation of China (No. 81772129), the 12th Five-Year Plan of China (No. 2012BAI11B00), and the Nature Science Foundation of Hubei Province (No. 2013CFA075).

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Zhan-fei Li and Xiang-jun Bai equally contributed to the design of the research and interpretation of the data. Yu-chang Wang, Qiang Zheng, Qin-xin Liu, Tao Liu, Xing-hua Liu and Xi-e XU performed the animal experiments and collected data. Yu-chang Wang and Wei Gao analyzed the data and cytokines. Molecular biological parts of the study were performed by Yu-chang Wang and Zhan-fei Li. Zhan-fei Li and Xiang-jun Bai supervised the project. All authors read and approved the final manuscript.

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Correspondence to Zhan-fei Li.

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Wang, Yc., Liu, Qx., Zheng, Q. et al. Dihydromyricetin Alleviates Sepsis-Induced Acute Lung Injury through Inhibiting NLRP3 Inflammasome-Dependent Pyroptosis in Mice Model. Inflammation 42, 1301–1310 (2019). https://doi.org/10.1007/s10753-019-00990-7

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