image: Knockout of the Sr-a1 gene abolished the up-regulation of macrophage phagocytosis by ozone. A: The protein levels of SR-A1 of BMDMs from the wild-type (WT) mice or Sr-a1−/− mice were detected by Western blotting (n = 3). B–D: BMDMs from the WT mice or Sr-a1−/− mice were induced to M1 type with LPS (100 ng/mL) and IFN-γ (50 ng/mL) for 24 h after differentiation and maturation in vitro. LPS (1 μg/mL) was used to stimulate BMDMs for 12 h to induce inflammation. Prior to this, BMDMs were pretreated with ozone (15 μg/mL) for 2 h, or with AICAR (300 μmol/L) or Compound C (20 μmol/L) for 15 min. Stained-labeled NETs (orange) were incubated with BMDMs processed as above in the confocal dish for 15 min, then rinsed lightly with ice-cold PBS three times, and photographed under confocal microscopy (B and C). NETs were labeled by Sytox Orange (n = 3). Scale bar, 50 μm. The protein levels of p-AMPK/AMPK in BMDMs (from WT mice) were detected by Western blotting (n = 3; D). E: The schematic illustration indicates that ozone enhances phagocytosis of NETs by macrophages through upregulation of SR-A1 via the AMPK pathway to alleviate septicemic lung injury. Data are presented as mean ± standard deviation. **P < 0.01 and ***P < 0.001 by one-way ANOVA followed by Tukey's tests for multiple comparisons. Abbreviations: CC, Compound C; SR-A1, scavenger receptor A1; AMPK, AMP-activated protein kinase; NETs, neutrophil extracellular traps; DAMPs, damage-associated molecular patterns; TF, tissue factor; MMP-9, matrix metalloproteinase-9; IL-1β, interleukin-1β; LPS, lipopolysaccharide; TLR4, Toll-like receptor 4; ns, not significant.
Credit: Journal of Biomedical Research
A cutting-edge study has identified medical ozone therapy as a promising new treatment for sepsis-induced acute lung injury (ALI). By enhancing the clearance of neutrophil extracellular traps (NETs) through the AMP-activated protein kinase (AMPK)/scavenger receptor A1 (SR-A1) pathway, this innovative approach could significantly improve survival rates and lung function in preclinical models, offering hope for patients with limited treatment options.
Sepsis, a severe and often fatal complication of infection, is a leading cause of both ALI and acute respiratory distress syndrome (ARDS). These conditions, which are associated with high mortality rates, remain challenging to treat due to the lack of effective therapies. NETs play a central role in the progression of sepsis, as they are involved in trapping pathogens but can also trigger excessive inflammation, exacerbating lung injury. The complexity of sepsis-induced ALI, driven by the interplay among inflammation, immune dysregulation, and coagulation, calls for innovative therapeutic strategies to better manage this critical condition.
In a study (DOI: 10.7555/JBR.38.20240038) from Nanjing Medical University, researchers have made significant progress in this area. Published in the Journal of Biomedical Research on November 28, 2024, the study details how medical ozone therapy targets the AMPK/SR-A1 axis to effectively clear NETs, significantly improving survival rates and lung function in mice suffering from sepsis-induced ALI. This work represents a critical step forward in the search for new treatments for this deadly condition.
The study provides an in-depth examination of the mechanisms behind ozone therapy's therapeutic effects on sepsis-induced ALI. Researchers discovered that ozone treatment reduced the formation of NETs, which was a key factor in the development of ALI. By activating the AMPK/SR-A1 pathway, ozone therapy enhanced the ability of macrophages to clear these harmful NETs, reducing inflammation and mitigating lung injury. The research also emphasizes the essential role of SR-A1: in knockout mice lacking SR-A1, ozone therapy failed to produce its protective effects, highlighting the receptor's critical role in mediating ozone's therapeutic impact. A comprehensive evaluation of lung function, blood flow, and protein levels further demonstrated the multifaceted benefits of ozone treatment, suggesting that it could become a valuable addition to existing therapies for sepsis-induced ALI.
Dr. Wen-Tao Liu, the principal investigator of the study, underscores the significance of these findings: Our research demonstrates that medical ozone therapy could dramatically improve the management of sepsis-induced ALI. By activating the AMPK/SR-A1 pathway, ozone therapy clears harmful NETs, restores immune balance, and reduces inflammation. This represents a promising new approach to critical care that could lead to better outcomes for patients suffering from sepsis.
The implications of this study are far-reaching. If subsequent research confirms these results in human trials, medical ozone therapy could become a viable and effective treatment for sepsis-induced lung injury, a condition currently with few treatment options. Ozone therapy's potential to improve survival and lung function could transform the management of sepsis, offering new hope for patients who face a bleak prognosis. As this promising therapy advances through further research, it may become a cornerstone in the fight against sepsis, reshaping how we treat this life-threatening condition.
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References
DOI
Original Source URL
https://doi.org/10.7555/JBR.38.20240038
Funding information
This work was supported by the National Natural Science Foundation of China (Grant Nos. 82271252, 82204542, and 81971047), the Lianyungang Science and Technology Program Project (Grant Nos. SF2122 and SF2214), the Scientific Research Project of Jiangsu Provincial Health Commission (Grant No. Z2021066), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grant No. 21KJB310019), and the Open Project of Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University (Grant No. XZSYSKF2021014).
About Journal of Biomedical Research
Journal of Biomedical Research is a free peer-reviewed open access journal dedicated to publishing high-quality research in all areas of the biological and medical sciences. Impact Factor 2.2, ISSN 1674-8301 CN 32-1810/R
Journal
Journal of Biomedical Research
Subject of Research
Not applicable
Article Title
Medical ozone alleviates acute lung injury by enhancing phagocytosis targeting NETs via AMPK/SR-A1 axis
Article Publication Date
29-May-2024
COI Statement
The authors declare that they have no competing interests.