By activating endothelium histone H4 mediates oleic acid-induced acute respiratory distress syndrome.
Summary
Extracellular histone H4 rises in plasma and BALF after OA challenge, correlating with ARDS severity, and directly activates endothelium (HS degradation, vWF release, P-selectin translocation, VE-cadherin loss). Anti-H4 mitigates edema and mortality, while TLRs and calcium mediate endothelial activation, positioning H4 as a pro-inflammatory/pro-thrombotic DAMP in ARDS.
Key Findings
- Extracellular histone H4 increases in plasma and BALF after OA, correlating with ARDS severity.
- Anti-H4 antibody protects against pulmonary edema and death; H4 pretreatment worsens outcomes.
- H4 activates endothelium (HS degradation, vWF release, P-selectin translocation, VE-cadherin reduction) via TLRs and calcium, enabling neutrophil activation.
Clinical Implications
Suggests potential for anti-H4 strategies or measurement of circulating histones as biomarkers to guide endothelial-protective interventions in severe lung injury.
Why It Matters
Pinpoints histone H4 as a targetable DAMP that drives endothelial injury and mortality in ARDS models, offering a mechanistic rationale for anti-histone or endothelium-stabilizing therapies.
Limitations
- Oleic acid model may not generalize to all ARDS etiologies
- No human validation or clinical biomarker thresholds provided
Future Directions
Assess circulating histone H4 as a prognostic biomarker in human ARDS; test anti-histone or endothelial-stabilizing agents in diverse injury models and early-phase trials.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical murine ARDS model with mechanistic interventions
- Study Design
- OTHER