Resveratrol Attenuates Inflammation in Acute Lung Injury through ROS-Triggered TXNIP/NLRP3 Pathway.
10.1007/s11655-025-4214-1
- Author:
Wen-Han HUANG
1
;
Kai-Ying FAN
2
;
Yi-Ting SHENG
1
;
Wan-Ru CAI
3
Author Information
1. Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Zhejiang Chinese Medical University, the Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
2. Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
3. Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Zhejiang Chinese Medical University, the Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China. caiwanru@aliyun.com.
- Publication Type:Journal Article
- Keywords:
NOD-, LRR- and pyrin domin-containing associated protein 3;
acute lung injury;
inflammation;
reactive oxygen species;
resveratrol
- MeSH:
Acute Lung Injury/metabolism*;
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism*;
Animals;
Resveratrol/pharmacology*;
Reactive Oxygen Species/metabolism*;
Inflammation/complications*;
Mice, Inbred C57BL;
Carrier Proteins/metabolism*;
Signal Transduction/drug effects*;
Lipopolysaccharides;
Thioredoxins/metabolism*;
Mice;
Lung/drug effects*;
Male;
Cell Line;
Interleukin-1beta/metabolism*;
Cell Cycle Proteins;
Stilbenes/therapeutic use*
- From:
Chinese journal of integrative medicine
2025;31(12):1078-1086
- CountryChina
- Language:English
-
Abstract:
OBJECTIVE:To evaluate the protective effects of resveratrol against acute lung injury (ALI) and investigate the potential mechanisms underlying the reactive oxygen species (ROS)-triggered thioredoxin-interacting protein (TXNIP)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathway.
METHODS:C57BL/6 mice and J774A.1 cells were selected as the research subjects. Thirty Mice were randomly divided into 5 groups of 6 in each group: control with 0.9% saline, 5 mg/kg lipopolysaccharide (LPS) 24 h, 25 mg/kg resveratrol + 5 mg/kg LPS, 100 mg/kg resveratrol + 5 mg/kg LPS, and 4 mg/kg NLRP3 inhibitor CY-09 + 5 mg/kg LPS. For cell stimulation, cells were pretreated with 5 and 20 µmol/L resveratrol for 2 h, and stimulated with or without 1 µg/mL LPS and 3 mmol/L ATP for 2 h. The antioxidant N-acetyl-L-cysteine (NAC, 2 µmol/L) was used as the positive control group. Hematoxylin and eosin staining was used to evaluate the degree of lung LPS-induced tissue damage, and enzyme-linked immunosorbent assay was used to evaluate the contents of interleukin-1 β (IL-1 β) and IL-18 in the serum and cell supernatant. ROS and malondialdehyde (MDA) levels in the lung tissue were detected using the corresponding kits. Western blotting was used to detect the expressions of TXNIP, high-mobility group box 1 (HMGB1), NLRP3, as well as cysteine-aspartic acid protease 1 (caspase-1) and gasdermin D (GSDMD) along with their cleaved forms in lung tissue. Additionally, reverse transcription quantitative polymerase chain reaction was performed to analyze the expression of related inflammatory cytokines. ROS content was detected using flow cytometry and confocal laser microscopy. Mitochondrial morphological changes were observed using transmission electron microscopy, and HMGB1 expression was detected using immunofluorescence.
RESULTS:Resveratrol significantly alleviated LPS-induced lung damage with reduced inflammation, interstitial edema, and leukocyte infiltration (P<0.01). It also decreased serum levels of IL-1 β and IL-18 (P<0.05), while downregulating the expressions of NLRP3, IL-6, and other inflammatory markers at both the protein and mRNA levels (P<0.05). Notably, the higher dose (100 mg/kg) demonstrated a better effect than the lower dose (25 mg/kg). In macrophages, resveratrol reduced IL-1 β and IL-18 following LPS and ATP stimulation, suppressed HMGB1 translocation, and inhibited formation and activation of the NLRP3 inflammasome (P<0.05 or P<0.01). These anti-inflammatory effects were mediated through the suppression ROS accumulation (P<0.01) and mitochondrial dysfunction. Transmission electron microscopy revealed that resveratrol preserved mitochondrial structure, preventing the mitochondrial damage seen in LPS-treated groups (P<0.01). The expressions of cleaved caspase-1, cleaved GSDMD, and cytoplasmic HMGB1 were all reduced following resveratrol treatment (P<0.01). Moreover, resveratrol inhibited dissociation of TXNIP from thioredoxin, blocking subsequent activation of NLRP3 and downstream inflammatory cytokines (P<0.01). Similarly, the higher concentration of resveratrol (20 µ mol/L) exhibited superior efficacy in vitro.
CONCLUSION:Resveratrol can reduce the inflammatory response following ALI and inhibit the activation of NLRP3 inflammasome and the level of HMGB1 in the cytoplasm by inhibiting ROS overproduction.
