Acute Respiratory Distress Syndrome (ARDS): Mechanism

Definition and Diagnostic Criteria (Berlin 2012)

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

Core Pathological Process: Diffuse Alveolar Damage (DAD)

Phase 1 — Exudative (Days 0–7)

1. Macrophage activation — Alveolar macrophages recognize PAMPs/DAMPs via Toll-like receptors (TLR) and pattern recognition receptors (PRR), switching to the M1 (pro-inflammatory) phenotype. They release:
   • TNF-α, IL-1β, IL-6, IL-8 (CXCL8)
   • Reactive oxygen species (ROS)
   • Platelet-activating factor
2. Neutrophil recruitment and sequestration — IL-8 and complement fragments (C5a) drive massive neutrophil recruitment into alveolar capillaries. Activated neutrophils undergo cytoskeletal rearrangements, becoming less deformable and physically sequestering in the narrow alveolar capillaries. Once adherent (via ICAM-1/β₂-integrin interactions), they transmigrate into the interstitium and alveolar space.
3. Neutrophil effector mechanisms — Extravasated neutrophils cause epithelial and endothelial injury through:
   • Proteases (elastase, matrix metalloproteinases) — degrade basement membrane
   • ROS / oxidants — oxidative stress to cell membranes
   • Myeloperoxidase (MPO) — generates hypochlorous acid
   • Neutrophil extracellular traps (NETs) — trap microbes but also damage endothelium and activate platelets
4. Platelet–neutrophil complexes — Activated platelets bind neutrophils via P-selectin/PSGL-1, amplifying ROS and NET release, further injuring the alveolocapillary membrane.
5. T-cell imbalance — Pro-inflammatory macrophages shift T-cell responses toward Th17 (↑ IL-17) and away from T-regulatory cells (↓ IL-10, ↓ TGF-β), sustaining the inflammatory milieu and suppressing resolution.

Phase 2 — Proliferative (Days 3–14)

• Type II pneumocyte hyperplasia — surviving type II cells proliferate to repopulate denuded alveolar walls and restore surfactant production
• Fibroblast activation — myofibroblasts migrate into alveolar spaces and interstitium; fibronectin and TGF-β drive collagen deposition
• Inflammation may partially resolve with macrophage phenotype shift toward M2 (anti-inflammatory, pro-repair)
• Lung function may begin to improve; some patients wean from ventilation

Phase 3 — Fibrotic (Day 14+)

• Extensive intra-alveolar fibrosis replaces the hyaline membrane exudate
• Persistent architectural distortion → chronic restrictive physiology, impaired gas exchange
• Occurs in severe cases; associated with prolonged ventilator dependence and worse long-term outcomes
• Patients who survive may have permanent exercise intolerance and reduced quality of life

Immunothrombosis

Gas Exchange Failure: Physiological Summary

Alveolar flooding + surfactant loss
        ↓
Alveolar collapse (atelectasis) + low compliance
        ↓
Intrapulmonary shunt (perfusion without ventilation)
        ↓
Refractory hypoxemia (PaO₂/FiO₂ < 300)
        ↓
Compensatory hyperventilation → hypocapnia (early)
        ↓
Respiratory muscle fatigue → hypercapnic respiratory failure (late)

Pulmonary Vascular Effects

• Hypoxic vasoconstriction + vascular remodeling → pulmonary hypertension
• Increased right ventricular afterload → possible RV strain/cor pulmonale
• Microvascular thrombosis further raises pulmonary vascular resistance

Pathogenesis Diagram

Key Mediators Summary