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Memantine Alleviates Acute Lung Injury Via Inhibiting Macrophage Pyroptosis
Hongdou Ding1,2, Jie Yang1,2, Linsong Chen1,2
1Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Abstract:
Acute lung injury (ALI) is caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis and trauma. Alveolar macrophages are the main and critical leukocytes in the airspace, and through the synthesis and release of various inflammatory mediators critically influence the development of ALI following infection and non-infectious stimuli. There is increasing recognition that inflammation and cell death reciprocally affect each other, which forms an auto-amplification loop of these two factors, and in turn, exaggerates inflammation. Therefore, pharmacological manipulation of alveolar macrophage death signals may serve as a logical therapeutic strategy for ALI. In this study, we demonstrate that memantine, a N-methyl-D-aspartic acid receptor (NMDAR) antagonist, through suppressing Ca2+ influx and subsequent ASC oligomerization inhibits macrophage Nlrp3 inflammasome activation and pyroptosis, therefore, alleviates ALI in septic mice. This finding explores a novel application of memantine, an FDA already approved medication, in the treatment of ALI, which is currently lacking effective therapy.
Insights
Memantine, an N-methyl-D-aspartic acid receptor antagonist, inhibits inflammasome activation and pyroptosis in macrophages. This novel approach alleviates acute lung injury (ALI) in septic mice, offering a potential new therapy.
Area of Science:
- Immunology
- Pharmacology
- Pulmonary Medicine
Background:
- Acute lung injury (ALI) involves inflammation and cell death, particularly in alveolar macrophages.
- This creates an auto-amplification loop, worsening the condition.
- Targeting macrophage death signals presents a potential therapeutic strategy for ALI.
Purpose of the Study:
- To investigate the therapeutic potential of memantine in treating ALI.
- To explore memantine's mechanism in modulating macrophage inflammasome activation and pyroptosis.
Main Methods:
- Utilized a mouse model of sepsis-induced ALI.
- Administered memantine, an N-methyl-D-aspartic acid receptor (NMDAR) antagonist.
- Assessed inflammasome activation, pyroptosis, and ALI severity.
Main Results:
- Memantine suppressed Ca2+ influx and ASC oligomerization.
- Inhibition of Nlrp3 inflammasome activation and pyroptosis in macrophages was observed.
- Memantine treatment alleviated ALI in septic mice.
Conclusions:
- Memantine effectively inhibits Nlrp3 inflammasome activation and pyroptosis in macrophages.
- Memantine demonstrates therapeutic potential for ALI by targeting macrophage death pathways.
- This study suggests a novel application for the FDA-approved drug memantine in treating ALI.
