Acute Respiratory Distress Syndrome (ARDS): Mechanism

Definition & Diagnostic Criteria (Berlin Definition)

• Bilateral infiltrates on CXR or CT (not fully explained by pleural effusions, atelectasis, or nodules)
• PaO₂/FiO₂ ratio < 300 (mild: 200–300; moderate: 100–200; severe: <100) with PEEP ≥ 5 cm H₂O
• Onset within 7 days of a known clinical insult
• Not fully explained by heart failure or fluid overload

Core Pathophysiology: The Alveolar-Capillary Barrier

• Direct injury (e.g., inhaled toxins, gastric aspiration, pneumonia)
• Indirect/systemic injury (e.g., sepsis-mediated mediator release reaching the lung via the bloodstream)

Step-by-Step Mechanistic Cascade

1. Initiating Insult → Innate Immune Activation

• TNF-α, IL-1β, IL-6, IL-8 (CXCL8)

2. Cytokine Storm

3. Neutrophil Recruitment & Activation — The Central Effector

• Reactive oxygen species (ROS) and reactive nitrogen species (RNS) → oxidative damage to epithelium and endothelium
• Proteases (elastase, matrix metalloproteinases) → degrade basement membranes and tight junctions
• Myeloperoxidase (MPO) → further oxidative injury
• Neutrophil extracellular traps (NETs) → ensnare pathogens but also damage endothelial cells and trigger immunothrombosis

4. Alveolar Epithelial Injury

• Type I pneumocytes (covering ~95% of alveolar surface) are highly susceptible — their destruction floods the alveolus with protein-rich edema fluid
• Type II pneumocyte injury has compounding effects:
  • Loss of surfactant production → alveolar collapse and dramatically increased surface tension
  • Loss of alveolar repair capacity (type II cells are the progenitors of type I)
  • Impaired active ion transport (Na⁺-K⁺-ATPase) → failure of edema clearance

5. Pulmonary Endothelial Injury → Non-Cardiogenic Edema

• Protein-rich exudate floods the alveolar space (pulmonary edema with high protein content — unlike the transudate of cardiogenic edema)
• Hydrostatic pressure is normal (wedge pressure < 18 mmHg), distinguishing ARDS from heart failure
• Fibrinogen enters the alveolus and polymerizes into hyaline membranes — a pathological hallmark on histology (diffuse alveolar damage, DAD)

6. Surfactant Failure → Atelectasis

• Progressive alveolar collapse (atelectasis)
• V/Q mismatch and intrapulmonary shunting
• Refractory hypoxemia (the defining clinical feature)

7. Coagulation Dysregulation

• Pro-inflammatory cytokines trigger tissue factor expression on endothelium → local fibrin deposition and microthrombi
• Simultaneously, fibrinolysis is impaired (elevated PAI-1)
• Result: immunothrombosis in pulmonary microvasculature → further V/Q mismatch and dead-space physiology

Phases of ARDS

Mechanical Ventilation as a Secondary Injury (Ventilator-Induced Lung Injury, VILI)

• Cyclic stretch → mechanical activation of NF-κB → further cytokine release
• Atelectrauma (repetitive opening and closing of unstable alveoli)
• Biotrauma → cytokines leak from the lung into the systemic circulation → MODS (multiple organ dysfunction syndrome)

Gravitational Distribution of Injury

• Dependent zones: consolidated/fluid-filled, contributing to shunt
• Non-dependent zones: relatively aerated but small ("baby lung")
• Intermediate zones: atelectatic but potentially recruitable

Pathophysiology Diagram

Summary: Key Mechanistic Steps

Initiating insult (sepsis, pneumonia, trauma)
          ↓
Macrophage activation (TLR/PRR) → Cytokine storm (TNF-α, IL-1β, IL-6, IL-8)
          ↓
Neutrophil recruitment → ROS, proteases, NETs
          ↓
Alveolar-capillary barrier disruption
    ├── Endothelial injury → Protein-rich edema floods alveoli
    ├── Type I pneumocyte loss → Loss of gas exchange surface
    └── Type II pneumocyte loss → Surfactant failure + impaired repair
          ↓
Hyaline membrane formation (diffuse alveolar damage)
          ↓
Surfactant deficiency → Alveolar collapse → V/Q mismatch → Shunt
          ↓
Refractory hypoxemia + reduced lung compliance (↓ΔV/ΔP)
          ↓
If uncontrolled → Fibroproliferative phase → Fibrosis / MODS