Metformin Effects on Acute Lung Injury in Sepsis

Sepsis often precipitates acute lung injury through a cascade of dysregulated inflammation, endothelial dysfunction and epithelial cell apoptosis, culminating in impaired gas exchange and high mortality. Metformin, a widely used antidiabetic agent, has emerged as a promising repurposed therapy in sepsis-associated lung injury by virtue of its ability to activate AMP-activated protein kinase (AMPK), suppress pro-inflammatory pathways and preserve barrier integrity. In experimental models, metformin attenuates endoplasmic reticulum stress and apoptosis in alveolar epithelial cells, enhances macrophage-mediated clearance of apoptotic debris and restores mitochondrial function. Concurrently, it modulates cytoskeletal dynamics in pulmonary microvascular endothelium, reducing hyperpermeability and neutrophil accumulation. By inhibiting key mediators such as nuclear factor-κB and the NLRP3 inflammasome, and by upregulating sirtuin-1 and other protective mediators, metformin mitigates endothelial pyroptosis and dampens excessive cytokine release. These multimodal actions have translated into reduced lung oedema, preservation of alveolar capillary permeability and improved survival in animal sepsis models. While retrospective clinical data hint at improved outcomes among metformin-treated patients with sepsis and diabetes, robust prospective trials are required to determine optimal dosing, timing and patient selection in the intensive care setting.

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Metformin Effects on Acute Lung Injury in Sepsis publication trend

The graph below shows the total number of articles in metformin effects on acute lung injury in sepsis across all publications each year (not limited to Nature Index journals).

Technical terms

Sepsis: A life-threatening organ dysfunction caused by a dysregulated host response to infection.

Acute lung injury (ALI): A syndrome characterised by rapid onset of widespread inflammation in the lung, leading to impaired oxygenation and increased vascular permeability.

AMP-activated protein kinase (AMPK): A cellular energy sensor that regulates metabolic homeostasis and modulates inflammatory and stress responses.

Endothelial hyperpermeability: Increased leakage of plasma and proteins through the vascular endothelium, contributing to tissue oedema.

NLRP3 inflammasome: A multiprotein complex that activates inflammatory caspases and mediates maturation of pro-inflammatory cytokines such as interleukin-1β.

Pyroptosis: A form of programmed cell death characterised by inflammasome activation, caspase-1-mediated gasdermin D cleavage and cell lysis.

References

1. AMPK activation improves recovery from pneumonia-induced lung injury via reduction of er-stress and apoptosis in alveolar epithelial cells. Respiratory Research (2023).
2. Metformin alleviates lung-endothelial hyperpermeability by regulating cofilin-1/PP2AC pathway. Frontiers in Pharmacology (2023).
3. Metformin Alleviates LPS-Induced Acute Lung Injury by Regulating the SIRT1/NF-κB/NLRP3 Pathway and Inhibiting Endothelial Cell Pyroptosis. Frontiers in Pharmacology (2022).
4. Association Between Preadmission Metformin Use and Outcomes in Intensive Care Unit Patients With Sepsis and Type 2 Diabetes: A Cohort Study. Frontiers in Medicine (2021).