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An oxidized mogrol derivative alleviates LPS-induced acute lung injury in association with reduced NLRP3 inflam-masome-associated inflammatory responses in mice

ABSTRACT: Acute lung injury (ALI) is a severe inflammatory pulmonary disorder with high mor-bidity and limited treatment options available in clinical settings. Mogrosides, natural products derived from Siraitia grosvenorii, have been shown to exhibit protective effects against ALI, but structural optimization of their aglycone moiety, mogrol may provide opportunities to improve pharmacological efficacy. In this study, oxidized mogrol de-rivatives (MG-COOH and MG-CHO) were synthesized, and their anti-inflammatory activities were initially compared with those of natural mogrosides in lipopolysaccha-ride (LPS)‑stimulated MH-S cells. MG-COOH displayed the strongest activity among the compounds and was designated for comprehensive analysis of its protective po-tential and underlying mechanisms in the LPS-induced ALI model. MG-COOH effec-tively alleviated LPS-induced injury in lung, decreased pro-inflammatory cytokine re-lease, and reduced oxidative stress, showing greater efficacy than natural mogrosides. Transcriptomic analysis indicated that MG-COOH modulated genes involved in NF-κB, MAPK, PI3K-Akt, JAK-STAT, and NOD-like receptor pathways. Furthermore, MG-COOH reduced the expression of NLRP3, ASC, caspase-1, and IL-1β mRNA and protein in lung. In conclusion, the oxidized mogrol derivative MG-COOH exhibits en-hanced anti-ALI activity relative to natural mogrosides. The protective effect against ALI of MG-COOH is associated with reduced NLRP3 inflammasome-related inflam-matory responses in the lung, which serves as a pivotal node in multiple inflammatory signaling cascades.

ORGANISM(S): Mus musculus

PROVIDER: GSE347446 | GEO | 2026/09/17

REPOSITORIES: GEO

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Project description:Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), acting as one common sepsis-associated organ injury, induces uncontrolled and self-amplifies pulmonary inflammation. Given the lack of clinically effective approaches, the mortality rate of it still remains high. Suramin(SUR) was found to ameliorate sepsis associated ALI in our previous work. However, the underlying mechanism of its protective effects has not been clarified. Pyroptosis, categorized as an inflammatory form of programmed cell death, could aggravate lung inflammatory responses via inducing alveolar macrophages (AM) pyroptosis. Methods: MH-S AM cell line was stimulated with or without lipopolysaccharide (LPS) or suramin, and the differential expression genes (DEGs) were excavated using RNA sequencing (RNA-Seq). To identify the regulatory roles of these genes, pyroptosis-related genes (PRGs), GO/KEGG and GSEA analysis were conducted. We also performed WB, qRT-PCR and ELISA to validate the RNA-seq results and further expound the protective effect of suramin. Results: 624 DEGs were identified between CON and lipopolysaccharide (LPS) groups, and enrichment analysis of these genes revealed significantly enriched pathways that related to immune system and signal transduction. Meanwhile, 500 DEGs were identified in LPS/SUR+LPS group. In addition to the pathways mentioned above, IL-17 pathway and C-type lectin receptor signaling pathway were also enriched. All 6 pathways were connected with pyroptosis. Concurrently, the “DESeq2” R package was used to identify differentially expressed PRGs. Nod1, Nod2, interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), NLRP3 were upregulated under LPS stimulation. Then, in SUR+LPS group, Nod2, IL-6, IL-1, NLRP3 were downregulated. The validation results of WB, qRT-PCR, and ELISA showed: the protein and mRNA expression levels of NLRP3, caspase-1, GSDMD and the concentrations of IL-1, IL-18 were decreased when treated with suramin and LPS. Conclusion: Suramin could inhibit NLRP3/caspase-1/GSDMD canonical pyroptosis pathway in LPS-induced MH-S alveolar macrophages.

Project description:Multipotent stromal cells (MSCs) are currently in clinical trials for a number of inflammatory diseases. Recent studies have demonstrated the ability of MSCs to attenuate inflammation in rodent models of acute lung injury (ALI) suggesting that MSCs may also be beneficial in treating ALI. To better understand how human MSCs (hMSCs) may act in ALI, the lungs of immunocompetent mice were exposed to lipopolysaccharide (LPS) and 4 hr later bone marrow derived hMSCS were delivered by oropharyngeal aspiration (OA). Administration of hMSCs significantly reduced the expression of pro-inflammatory cytokines, neutrophil counts and total protein in bronchoalveolar lavage. There was a concomitant reduction in pulmonary edema as indicated by a decrease in lung wet/dry weight ratio. The anti-inflammatory effects of hMSCs were not dependent on localization to the lung, as intraperitoneal administration of hMSCs also attenuated LPS-induced inflammation in the lung. Microarray analysis revealed significant induction of TNF-α-induced protein 6 (TSG-6) expression by hMSCs 12 hr after OA delivery to LPS-exposed lungs. Knockdown of TSG-6 expression in hMSCs by RNA interference abrogated most of their anti-inflammatory effects. In addition, intra-pulmonary delivery of recombinant human TSG-6 reduced LPS-induced inflammation in the lung. These results show that hMSCs recapitulate the observed beneficial effects of rodent MSCs in animal models of ALI and suggest that the anti-inflammatory properties of hMSCs in the lung are explained, at least in part, by activation of hMSCs to secrete TSG-6. Eight- to 10-week-old female BALB/C mice were treated with either 1 mg/kg lipopolysaccharide (LPS) in 100 μl PBS or an equal volume of PBS, as vehicle control, by oropharyngeal aspiration (OA). Four hours after LPS exposure, 250,000 human multipotent stromal cells in 100 μl of PBS were given by OA and 30 min later a second dose of equal concentration was administered, for a total of 500,000 hMSC. As a control, 200 μl PBS was delivered as described above. After 12 h, total RNA was isolated from (A) lungs of LPS-exposed mice treated with either hMSCs (LPS+MSC) or PBS (LPS+PBS), and (B) lungs of PBS-exposed mice treated with hMSCs (PBS+MSC). To obtain additional controls, hMSCs were mixed in vitro with either LPS- (LPS+MSC in vitro mix) or PBS-exposed (PBS+MSC in vitro mix) mouse lungs just before RNA isolation. RNA samples containing mouse and human RNA were first analyzed for amount of human RNA based on human GAPDH signal from real-time RT PCR. Samples with similar human RNA content were used for both mouse and human microarrays

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An oxidized mogrol derivative alleviates LPS-induced acute lung injury in association with reduced NLRP3 inflam-masome-associated inflammatory responses in mice

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