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Glycine Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Regulating NLRP3 Inflammasome and NRF2 Signaling.

ABSTRACT: Glycine supplementation has been reported to alleviate lipopolysaccharide (LPS)-induced lung injury in mice. However, the underlying mechanisms responsible for this beneficial effect remain unknown. In the present study, male C57BL/6 mice were treated with aerosolized glycine (1000 mg in 5 mL of 0.9% saline) or vehicle (0.9% saline) once daily for 7 continuous days, and then were exposed to aerosolized LPS (5 mg in 5 mL of 0.9% saline) for 30 min to induce lung injury. Sera and lung tissues were collected 24 h post LPS challenge. Results showed that glycine pretreatment attenuated LPS-induced decreases of mucin at both protein and mRNA levels, reduced LPS-triggered upregulation of pro-inflammatory cytokines, such as tumor necrosis factor-? (TNF-?), interferons, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukins. Further study showed that glycine-reduced LPS challenge resulted in the upregulation of nuclear factor ?B (NF-?B), nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. In addition, LPS exposure led to the downregulation of NRF2 and downstream targets, which were significantly improved by glycine administration in the lung tissues. Our findings indicated that glycine pretreatment prevented LPS-induced lung injury by regulating both NLRP3 inflammasome and NRF2 signaling.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7146254 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Glycine Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Regulating NLRP3 Inflammasome and NRF2 Signaling.

Zhang Yunchang Y Ma Xiaoshi X Jiang Da D Chen Jingqing J Jia Hai H Wu Zhenlong Z Kim In Ho IH Yang Ying Y

Nutrients 20200226 3

Glycine supplementation has been reported to alleviate lipopolysaccharide (LPS)-induced lung injury in mice. However, the underlying mechanisms responsible for this beneficial effect remain unknown. In the present study, male C57BL/6 mice were treated with aerosolized glycine (1000 mg in 5 mL of 0.9% saline) or vehicle (0.9% saline) once daily for 7 continuous days, and then were exposed to aerosolized LPS (5 mg in 5 mL of 0.9% saline) for 30 min to induce lung injury. Sera and lung tissues were ...[more]

PMID: 32110933

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Project description:Objective: To investigate the mechanism of Tocilizumab (TCZ) in attenuating acute lung injury in rats with sepsis by regulating the S100A12/NLRP3 axis. Methods: A rat model of sepsis was constructed using cecal ligation and puncture (CLP). Rats were treated with TCZ, and their lung tissue was collected. H&E staining was used to detect pathologic damage to lung tissue, and lung wet/dry (W/D) weight ratio was measured to assess pulmonary edema. Lipid oxidation assay and superoxide dismutase (SOD) activity assay kits were used to measure malondialdehyde (MDA) and SOD levels. Primary rat pulmonary microvascular endothelial cells (MPVECs) were treated with lipopolysaccharide (LPS) to construct a rat model of sepsis, which was then treated with TCZ. The mRNA and protein expressions of S100A12/NLRP3 were detected by qRT-PCR and western blot, respectively. S100A12 knockdown and overexpression plasmids, and NLRP3 knockdown plasmids were constructed and transfected into sepsis cells to intervene in the levels of S100A12/NLRP3. The apoptosis rate was detected by apoptosis assay. The levels of IL-6, TNF-α, and IL-10 in cells and tissues were analyzed by ELISA. Results: Compared to the Sham group, the CLP group had increased W/D weight ratio of lung tissue, IL-6, TNF-α, and MDA levels, lowered IL-10 and SOD levels, and more severe tissue damage (all P<0.05). After TCZ treatment, the above indicators were improved. The expressions of S100A12/NLRP3 cells were increased in LPS-induced MPVECs, but decreased after TCZ treatment. LPS induced apoptosis, but TCZ reduced the apoptosis, weakened the secretion levels of IL-6 and TNF-α, and enhanced IL-10 secretion levels. Transfection to cause the overexpression of S100A12 or NLRP3 plasmid partially counteracted the effect of TCZ. Knockdown of S100A12 was transfected on the basis of overexpression of NLRP3, which weakened the countervailing effect of overexpressed NLRP3 on TCZ. Conclusion: TCZ has a therapeutic effect on lung injury in rats with sepsis by reducing the expressions of S100A12/NLRP3.

Project description:BackgroundAcute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in many critically ill patients. Although inflammasome activation plays an important role in the induction of acute lung injury (ALI) and ARDS, the regulatory mechanism of this process is still unclear. When cells are stimulated by inflammation, the integrity and physiological function of mitochondria play a crucial part in pyroptosis. However, the underlying mechanisms and function of mitochondrial proteins in the process of pyroptosis are largely not yet known. Here, we identified the 18-kDa translocator protein (TSPO), a mitochondrial outer membrane protein, as an important mediator regulating nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in macrophages during ALI.MethodsTSPO gene knockout (KO) and lipopolysaccharide (LPS)-induced ALI/ARDS mouse models were employed to investigate the biological role of TSPO in the pathogenesis of ARDS. Murine macrophages were used to further characterize the effect of TSPO on the NLRP3 inflammasome pathway. Activation of NLRP3 inflammasome was preformed through LPS + adenosine triphosphate (ATP) co-stimulation, followed by detection of mitochondrial membrane potential, reactive oxygen species (ROS) production, and cell death to evaluate the potential biological function of TSPO. Comparisons between two groups were performed with a two-sided unpaired t -test.ResultsTSPO- KO mice exhibited more severe pulmonary inflammation in response to LPS-induced ALI. TSPO deficiency resulted in enhanced activation of the NLRP3 inflammasome pathway, promoting more proinflammatory cytokine production of macrophages in LPS-injured lung tissue, including interleukin (IL)-1β, IL-18, and macrophage inflammatory protein (MIP)-2. Mitochondria in TSPO -KO macrophages tended to depolarize in response to cellular stress. The increased production of mitochondrial damage-associated molecular pattern led to enhanced mitochondrial membrane depolarization and pyroptosis in TSPO -KO cells.ConclusionTSPO may be the key regulator of cellular pyroptosis, and it plays a vital protective role in ARDS occurrence and development.

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Dataset Information

Glycine Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Regulating NLRP3 Inflammasome and NRF2 Signaling.

Publications

Glycine Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Regulating NLRP3 Inflammasome and NRF2 Signaling.

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