Mechanism of Acute Respiratory Distress Syndrome (ARDS)

Berlin Definition (2012)

Precipitating Causes

Phases of ARDS

Time course of ARDS - Harrison's Principles of Internal Medicine, 22E

Core Pathophysiology: The Alveolar-Capillary Barrier

The injured alveolus in ARDS (Harrison's Principles of Internal Medicine, 22E)

Phase 1: Exudative Phase (Days 0-7)

1. Initiation - Endothelial and Epithelial Injury

• Endothelial injury: disrupts tight junctions between capillary endothelial cells, increasing vascular permeability
• Epithelial injury: Type I pneumocytes (which cover 95% of the alveolar surface) are particularly vulnerable; their necrosis disrupts the epithelial barrier

2. Neutrophil Recruitment and Activation

Role of neutrophils in ARDS pathogenesis (Murray & Nadel's Textbook of Respiratory Medicine)

1. Transient leukopenia is often the earliest manifestation of ARDS - neutrophils sequester in the pulmonary capillaries even before hypoxemia develops
2. Activated neutrophils become mechanically "stiff" (via actin cytoskeleton remodeling) and cannot deform to pass through narrow pulmonary capillary segments (average capillary diameter < average neutrophil diameter)
3. Sequestered neutrophils migrate across the alveolar-capillary membrane - this can occur even without conventional adhesion molecules (L-selectin, β2-integrins)
4. Once in the alveolar space, activated neutrophils release a destructive arsenal:
   • Reactive oxygen species (ROS) - oxidative injury to membranes
   • Proteolytic enzymes - leukocyte elastase, matrix metalloproteinases
   • Cationic peptides (defensins)
   • Eicosanoids
   • Neutrophil extracellular traps (NETs) - chromatin-based networks that trap pathogens but also damage host tissue
   • Cytokines/chemokines - amplify the inflammatory response (TNF-α, IL-1β)

3. Alveolar Flooding and Edema Formation

• Protein-rich, exudative fluid floods the alveolar spaces
• This edema fluid contains fibrin, inflammatory cells, and plasma proteins
• Hypoxemia develops from ventilation-perfusion (V/Q) mismatch and intrapulmonary right-to-left shunting (blood perfuses non-ventilated, fluid-filled alveoli)
• Dead space increases substantially (sometimes to >60% of tidal volume), impairing CO2 elimination

4. Surfactant Dysfunction

• Alveolar flooding dilutes and inactivates surfactant
• Inflammatory mediators (especially phospholipase A2, elevated in pancreatitis-associated ARDS) enzymatically degrade surfactant phospholipids
• Loss of surfactant leads to increased alveolar surface tension, promoting alveolar collapse (atelectasis) and further worsening compliance and shunting
• Surfactant proteins (SP-A, SP-D) also have antimicrobial roles; their loss may impair host defense

5. Hyaline Membrane Formation

6. Coagulation Activation

• Tissue factor is expressed on injured epithelial cells
• Fibrin deposition in alveoli and pulmonary microvasculature impairs gas exchange
• Microvascular thrombosis reduces pulmonary blood flow and contributes to pulmonary hypertension

Phase 2: Proliferative Phase (Days 7-21)

• The neutrophil-predominant infiltrate shifts to a lymphocyte-predominant one
• Type II pneumocytes (which survived the initial injury better than Type I cells) proliferate along denuded alveolar basement membranes
• Type II cells synthesize new surfactant and differentiate into Type I pneumocytes to restore the epithelial lining
• Alveolar exudates begin to organize
• Many patients recover during this phase; others develop progressive injury and early fibrotic changes

Phase 3: Fibrotic Phase (Days 21+)

• Alveolar edema and inflammatory exudates are replaced by alveolar-duct and interstitial fibrosis
• Marked disruption of acinar architecture leads to emphysema-like changes with large bullae
• Intimal fibroproliferation in pulmonary microcirculation causes progressive vascular occlusion and pulmonary hypertension
• Physiologic consequences: increased pneumothorax risk, reduced compliance, increased dead space
• Lung biopsy evidence of fibrosis in any ARDS phase is associated with increased mortality

Physiologic Consequences of the Mechanism

Ventilator-Induced Lung Injury (VILI) - A Superimposed Mechanism

• Volutrauma: large tidal volumes preferentially overdistend the "baby lung" (the small fraction of normal-appearing alveoli), causing mechanical injury and increased permeability
• Barotrauma: high airway pressures cause pneumothorax, pneumomediastinum
• Atelectrauma: repetitive opening and closing of collapsed airway units generates high shear stresses at the interface of aerated and collapsed tissue
• Biotrauma: mechanical stretch triggers local cytokine release (TNF-α, IL-1β, IL-6, IL-8) and systemic inflammation, contributing to multi-organ dysfunction

Genetic and Host Factors

Summary Diagram of the Mechanism

Insult (sepsis, pneumonia, trauma, aspiration...)
        ↓
Alveolar macrophage + TLR activation
        ↓
Cytokine storm (TNF-α, IL-1β, IL-6, IL-8)
        ↓
Neutrophil sequestration & transmigration into alveoli
        ↓
Release of ROS, proteases, NETs
        ↓
Endothelial + Epithelial barrier disruption
        ↓
Protein-rich exudate floods alveoli
Surfactant degradation + hyaline membrane formation
Microvascular fibrin deposition
        ↓
Shunt + V/Q mismatch + dead space → Hypoxemia
Reduced compliance → Increased work of breathing
Pulmonary hypertension → RV dysfunction
        ↓
↙ Recovery (Type II cell proliferation, repair)
↘ Fibrosis (progressive vascular occlusion, bullae)

• Murray & Nadel's Textbook of Respiratory Medicine, Chapter 134 (ARDS - Etiology, Pathogenesis, Neutrophil Biology, VILI)
• Harrison's Principles of Internal Medicine, 22E, Chapter 312 (Clinical Course and Pathophysiology)
• Goldman-Cecil Medicine, Chapter 91 (Ventilatory Support and Lung-Protective Strategies)
• Sabiston Textbook of Surgery, Chapter on ARDS (Berlin Definition, Management)
• Robbins & Kumar Basic Pathology (Diffuse Alveolar Damage, Histopathology)