What is the pathogenesis of paraquat poisoning?

Pathogenesis of Paraquat Poisoning

Paraquat poisoning causes multi-organ toxicity through oxidative stress and free radical generation, with selective pulmonary accumulation leading to progressive lung injury and fibrosis that represents the primary cause of death. 1, 2

Primary Mechanism: Oxidative Injury

The fundamental pathogenic mechanism involves paraquat's redox cycling properties that generate toxic free radicals:

• Paraquat accumulates selectively in lung tissue where it undergoes cyclic reduction and oxidation reactions, producing superoxide radicals and depleting NADPH 1
• Free radical formation triggers lipid peroxidation of cellular membranes, causing direct cellular damage 1, 2
• Oxidative stress represents the dominant pathogenic mechanism, though the complete picture remains incompletely understood 2

Pulmonary-Specific Pathogenesis

The lungs bear the brunt of toxicity due to active uptake mechanisms:

• Active pulmonary accumulation occurs through a polyamine uptake system, creating a "deep compartment" with high local concentrations despite systemic clearance 1
• Diffuse alveolitis develops initially, followed by extensive and irreversible pulmonary fibrosis in the late phase 1, 2
• Respiratory failure from pulmonary fibrosis is the leading cause of death in paraquat poisoning 2

Multi-Organ Toxicity Patterns

Beyond the lungs, paraquat causes dose-dependent injury to multiple organ systems:

• Caustic burns of the upper digestive tract occur from direct contact, though their absence indicates better prognosis 1, 3
• Renal tubular necrosis develops in the majority of fatal cases, though isolated renal failure alone does not necessarily predict death 1, 3
• Hepatic injury manifests as cytolytic hepatitis in some cases 3
• Circulatory failure occurs with high-dose ingestion (>50 mg/kg), causing death within 72 hours 3

Additional Pathogenic Mechanisms

Recent research has identified multiple contributing pathways beyond simple oxidative stress:

• Inflammatory injury plays a significant role alongside oxidative damage 2
• Mitochondrial damage contributes to cellular dysfunction 2
• Loss of pulmonary surfactant impairs gas exchange 2
• Abnormal gene expression and cytokine network dysregulation perpetuate injury 2
• Imbalanced matrix metalloproteinases and tissue inhibitors drive fibrotic progression 2
• Autophagy-dependent ferroptosis (ferritinophagy) has been identified as a mechanism in neurological toxicity from paraquat exposure 4

Critical Pathogenic Factor: Oxygen Paradox

Supplemental oxygen dramatically worsens paraquat toxicity by accelerating free radical production 5, 6, 7:

• Oxygen enhances the redox cycling of paraquat, increasing superoxide generation
• This explains why oxygen should only be given if SpO2 falls below 85% and stopped if it rises above 88% 6, 7

Dose-Response Relationship

The quantity absorbed determines the clinical syndrome:

• >50 mg/kg causes fulminant multi-organ failure with death in 2-3 days from circulatory collapse 1, 3
• 35-50 mg/kg produces delayed death over several weeks from progressive pulmonary fibrosis 3
• ≥4 mg/kg causes respiratory distress and renal dysfunction with variable outcomes 8
• Plasma paraquat concentrations are the most important prognostic indicator, with specific thresholds predicting survival 1, 3

Route-Dependent Pathogenesis

The route of exposure significantly affects toxicity:

• Intravenous injection produces the most rapid and severe toxicity, with death occurring within 5 days despite aggressive treatment 9
• Oral ingestion is the most common route, with toxicity modified by food in the stomach that can adsorb and neutralize some paraquat 3
• Inhalation and dermal exposure generally produce less severe systemic toxicity, with all four inhalation cases in one series surviving 3