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Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
Melatonin alleviates sepsis-induced acute lung injury by inhibiting necroptosis via reducing circulating mtDNA
Yuce Peng1, Jia Xu2, Lingyu Wei2
1Department of Cardiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Background:
Sepsis is a life-threatening condition that often leads to severe complications, including acute lung injury (ALI), which carries high morbidity and mortality in critically ill patients. Melatonin (Mel) has shown significant protective effects against sepsis-induced ALI, but its precise mechanism remains unclear.
Methods:
A cecal ligation and puncture (CLP) model was used to induce sepsis in male C57BL/6 mice, which were divided into four groups: Control, Sham, CLP, and CLP + Mel. ALI severity was evaluated via hematoxylin and eosin (H&E) staining, lung wet/dry ratio, and serum biomarkers (SP-D, sRAGE). Inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured in serum and bronchoalveolar lavage fluid using ELISA. Circulating mitochondrial DNA (mtDNA) subtypes (D-loop, mt-CO1, mMito) were quantified by real-time PCR. TUNEL staining was performed to assess lung cell apoptosis. Necroptosis and STING pathway activation were analyzed via Western blot and immunofluorescence.
Results:
Sepsis led to increased circulating mtDNA levels and activation of necroptosis signaling pathways. Melatonin treatment alleviated sepsis-induced ALI, improving survival, reducing inflammatory cytokines and mtDNA release, and suppressing necroptosis. Intraperitoneal injection of mtDNA in mice activated necroptosis, while RIP1 inhibitor Nec-1 counteracted mtDNA-induced lung damage and necroptosis in sepsis-induced ALI. Additionally, melatonin significantly inhibited STING pathway activation. Further experiments revealed that STING modulation influenced necroptosis protein expression and mediated melatonin's protective effects in sepsis-induced ALI.
Conclusion:
Melatonin mitigates sepsis-induced ALI by suppressing necroptosis through inhibition of STING activation and reduction of mtDNA release. These findings suggest melatonin as a potential therapeutic strategy for sepsis-induced ALI.
Insights
Melatonin protects against sepsis-induced acute lung injury (ALI) by inhibiting necroptosis and STING pathway activation. This study reveals melatonin
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Sepsis frequently causes acute lung injury (ALI), a condition with high mortality.
- Melatonin (Mel) demonstrates protective effects against sepsis-induced ALI, but its mechanism is not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which melatonin mitigates sepsis-induced ALI.
- To investigate the role of necroptosis and the STING pathway in melatonin's protective effects.
Main Methods:
- A cecal ligation and puncture (CLP) mouse model was used to induce sepsis.
- ALI severity was assessed using histological analysis, lung wet/dry ratio, and serum biomarkers.
- Inflammatory cytokines, circulating mitochondrial DNA (mtDNA), necroptosis, and STING pathway activation were quantified.
Main Results:
- Sepsis increased circulating mtDNA and activated necroptosis and STING pathways.
- Melatonin treatment reduced ALI severity, inflammation, and mtDNA release, while suppressing necroptosis.
- Melatonin inhibited STING activation, which was crucial for its protective effects against sepsis-induced ALI.
Conclusions:
- Melatonin mitigates sepsis-induced ALI by suppressing necroptosis via STING pathway inhibition and reduced mtDNA release.
- Melatonin presents a potential therapeutic strategy for managing sepsis-induced ALI.
