Paraquat-Induced Lung Injury Mechanisms and Therapeutics

Paraquat is a potent bipyridyl herbicide that selectively accumulates in pulmonary tissue, undergoing redox cycling to generate reactive oxygen species (ROS) and deplete cellular antioxidants. This leads to alveolar epithelial and endothelial cell damage, mitochondrial dysfunction and the release of danger signals such as HMGB1. Subsequent engagement of pattern recognition receptors and activation of inflammatory kinases—including p38 MAPK and NF-κB—drive neutrophil recruitment, cytokine storm and progressive fibrosis. In the absence of a specific antidote, therapeutic strategies focus on limiting oxidant injury, modulating key signalling pathways and enhancing endogenous antioxidant defences. Approaches under investigation include targeted haemoperfusion, small-molecule inhibitors of proinflammatory kinases, repurposed metabolic modulators such as AMPK activators, anti-ageing proteins like klotho and intrinsic antioxidants. These interventions aim to reduce mortality, attenuate acute injury and prevent long-term fibrotic remodelling in at-risk populations worldwide.

Research from Nature Portfolio

Recent studies have delineated a critical HMGB1–TLR4–IL-23–IL-17A signalling axis in murine models of paraquat exposure. Release of HMGB1 from injured alveolar cells activates TLR4 on innate immune cells, driving IL-23 production by antigen-presenting cells and expansion of IL-17A-producing γδT lymphocytes. Targeting any component of this cascade—through neutralising antibodies or genetic deletion—markedly reduced neutrophil infiltration and mitigated lung damage, highlighting multiple therapeutic entry points. In parallel, untargeted metabolomic profiling has uncovered the protective spectrum of the intrinsic antioxidant 5-hydroxy-1-methylhydantoin. Pretreatment restored superoxide dismutase activity, rebalanced glutathione and taurine metabolism, and corrected disruptions in the tricarboxylic acid cycle. These findings underscore both signalling and metabolic targets for future drug development.

Paraquat-Induced Lung Injury Mechanisms and Therapeutics publication trend

The graph below shows the total number of articles in paraquat-induced lung injury mechanisms and therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): chemically reactive molecules containing oxygen that can damage lipids, proteins and DNA when produced in excess.

Redox cycling: repetitive transfer of electrons between a compound and cellular reductants, leading to continuous generation of ROS and depletion of antioxidants.

High-mobility group box 1 (HMGB1): nuclear protein released upon cell injury that acts extracellularly as a proinflammatory signal.

Toll-like receptor 4 (TLR4): innate immune receptor that recognises endogenous danger signals and microbial components, triggering inflammatory pathways.

Interleukin-17A (IL-17A): proinflammatory cytokine produced by various lymphoid cells that promotes neutrophil recruitment and activation.

p38 mitogen-activated protein kinase (p38 MAPK): stress-activated kinase that regulates inflammatory gene expression and apoptosis.

Adenosine monophosphate-activated protein kinase (AMPK): cellular energy sensor kinase that modulates metabolism, autophagy and inflammation when activated.

Nuclear factor κB (NF-κB): transcription factor central to the control of genes involved in inflammation, immunity and cell survival.

References

1. Paraquat: model for oxidant-initiated toxicity.. Environmental Health Perspectives (1984).
2. HMGB1-TLR4-IL23-IL17A axis promotes paraquat-induced acute lung injury by mediating neutrophil infiltration in mice. Scientific Reports (2017).
3. Toxicology of paraquat and pharmacology of the protective effect of 5-hydroxy-1-methylhydantoin on lung injury caused by paraquat based on metabolomics. Scientific Reports (2020).
4. Metformin Activates the Protective Effects of the AMPK Pathway in Acute Lung Injury Caused by Paraquat Poisoning. Oxidative Medicine and Cellular Longevity (2019).
5. Klotho Alleviates Lung Injury Caused by Paraquat via Suppressing ROS/P38 MAPK‐Regulated Inflammatory Responses and Apoptosis. Oxidative Medicine and Cellular Longevity (2020).
6. Early Hemoperfusion May Improve Survival of Severely Paraquat-Poisoned Patients. PLOS ONE (2012).