Acute Respiratory Distress Syndrome (ARDS) — Mechanism

1. Initiating Insults

2. The Alveolar-Capillary Membrane Breakdown

• The capillary endothelium
• The basement membrane
• The alveolar epithelium (type I and type II pneumocytes)

3. Neutrophil Recruitment and Activation — The Core Driver

1. Systemic activation: The initiating insult activates the innate immune system — pattern-recognition receptors (TLRs, PRRs) on macrophages detect DAMPs (damage-associated molecular patterns) or PAMPs (pathogen-associated patterns).
2. Cytokine storm: Activated alveolar macrophages release pro-inflammatory cytokines — TNF-α, IL-1β, IL-6, IL-8 — into the alveolar space and systemic circulation.
3. Neutrophil margination and sequestration: IL-8 and other chemokines recruit neutrophils into the pulmonary capillaries. Neutrophils become stiff, sequester in capillary beds, and adhere to activated endothelium via upregulated adhesion molecules (ICAM-1, selectins).
4. Transendothelial and transepithelial migration: Neutrophils migrate into the interstitium and alveolar space.
5. Toxic mediator release: Activated neutrophils release:
   • Reactive oxygen species (ROS) — oxidative damage to lipid membranes
   • Proteases (elastase, matrix metalloproteinases, cathepsins) — degrade the extracellular matrix and tight junctions
   • Neutrophil extracellular traps (NETs) — webs of chromatin and enzymes that amplify injury
   • Myeloperoxidase (MPO) — generates hypochlorous acid
6. Barrier destruction: Together these mediators destroy tight junction proteins (occludin, claudins, ZO-1) of both endothelium and epithelium, producing the high-permeability leak.

4. Surfactant Dysfunction

• Diluted by protein-rich edema fluid
• Inactivated by phospholipase A2 (released from activated neutrophils and pancreatic/systemic sources) — phospholipase A2 enzymatically degrades surfactant phospholipids
• Oxidised by ROS

5. Phases of Histopathological Injury: Diffuse Alveolar Damage (DAD)

• Protein-rich, fibrin-containing alveolar edema
• Sloughing of type I pneumocytes — the alveolar basement membrane is denuded
• Formation of hyaline membranes — eosinophilic deposits of fibrin, necrotic cell debris, and protein lining the alveolar walls (pathognomonic of DAD)
• Neutrophilic infiltration of the interstitium and alveolar space
• Capillary microthrombi formation

• Type II pneumocyte hyperplasia — attempt to repopulate denuded epithelium
• Fibroblast proliferation and early fibrosis begins
• Macrophage-mediated clearance of debris
• Restoration of surfactant production if recovery proceeds

• Permanent fibrotic remodelling of alveoli
• Loss of lung architecture, reduced compliance
• Not all patients progress to this phase — good recovery is possible

6. Coagulation and Microvascular Thrombosis

• Damaged endothelium exposes tissue factor → activates the extrinsic coagulation cascade
• Fibrin deposited within capillaries and alveolar spaces
• Plasminogen activator inhibitor-1 (PAI-1) is elevated → suppresses fibrinolysis
• Capillary microthrombi worsen ventilation-perfusion (V/Q) mismatch and contribute to pulmonary hypertension

7. Impaired Alveolar Fluid Clearance

• Injury to type I and II cells impairs active Na⁺ transport
• Protein-rich edema accumulates and cannot be cleared
• Catecholamines, which normally upregulate Na⁺ transport, lose their effect in the injured epithelium

8. Angiopoietins and Vascular Dysregulation

• Angiopoietin-1 (Ang-1): stabilises endothelial junctions — protective
• Angiopoietin-2 (Ang-2): released from Weibel-Palade bodies during endothelial activation → destabilises junctions, promotes vascular leak and upregulates inflammatory adhesion molecules

9. Physiological Consequences

10. Two Biological Phenotypes

• Hyperinflammatory (phenotype 2): high IL-6, IL-8, Ang-2, low protein C; higher mortality (~40%), may respond to higher PEEP and statin therapy
• Hypoinflammatory (phenotype 1): milder biomarker elevation, lower mortality (~20%)

Summary Pathway

Systemic insult (sepsis, trauma, aspiration…)
        ↓
Innate immune activation → macrophage cytokine release (TNF-α, IL-1β, IL-8)
        ↓
Neutrophil sequestration in pulmonary capillaries
        ↓
ROS, proteases, NETs → Alveolar-capillary barrier destruction
        ↓
High-permeability edema floods alveoli
        ↓
Surfactant inactivation → alveolar collapse
Impaired Na⁺ transport → edema accumulation
Procoagulant state → microvascular thrombosis
        ↓
DAD: hyaline membranes, type I cell sloughing, type II hyperplasia
        ↓
Severe hypoxemia (refractory to O₂), decreased compliance, pulmonary HTN
        ↓
Respiratory failure → mechanical ventilation required

• Murray & Nadel's Textbook of Respiratory Medicine — Chapter 134 (Etiology and Pathogenesis of ARDS)
• Murray & Nadel's Textbook of Respiratory Medicine — Chapter 94 (Diffuse Alveolar Damage)
• Goldman-Cecil Medicine — Chapter 91 (ARDS)
• Sabiston Textbook of Surgery — Critical Care chapter