Acute Respiratory Distress Syndrome (ARDS): Mechanism

Triggers and Initial Injury

• Harrison's Principles of Internal Medicine 22E, p. 2343

Phase 1: Exudative Phase (Days 0-7)

Cellular and molecular events

1. Initial insult activates Toll-like receptors on type I alveolar epithelial cells (ATI) and resident alveolar macrophages, triggering release of proinflammatory chemokines (IL-1, IL-6, IL-8, TNF-α, leukotriene B2).
2. Neutrophil recruitment: Chemokines recruit circulating polymorphonuclear (PMN) leukocytes into the pulmonary interstitium and alveolar space. Activated neutrophils release:
   • Proteases (elastase, metalloproteinases) - degrade the basement membrane
   • Reactive oxygen species (ROS) - cause direct oxidative injury
   • Neutrophil extracellular traps (NETs) - trap pathogens but also damage epithelium
3. Monocyte and platelet involvement: Monocytes migrate into the lung and cause epithelial cell apoptosis via IFN-β-dependent release of TRAIL (TNF-related apoptosis-inducing ligand). Activated platelets form aggregates with PMNs and monocytes, amplifying injury. Red blood cells release cell-free hemoglobin, further exacerbating oxidative damage.
4. Endothelial and epithelial barrier failure: Endothelial tight junctions widen and intercellular junctions disrupt. Type I pneumocytes undergo necrosis. The result is massive protein-rich edema fluid flooding the interstitium and alveolar spaces.
5. Surfactant dysfunction: Alveolar edema washes out and inactivates surfactant, causing alveolar collapse (atelectasis) and a dramatic reduction in lung compliance. Phospholipase A2 (elevated in pancreatitis-related ARDS) directly degrades surfactant phospholipids.
6. Hyaline membrane formation: Condensed plasma proteins, fibrin, and cellular debris aggregate in the air spaces to form hyaline membrane whorls - the histologic hallmark of diffuse alveolar damage (DAD).
7. Vascular injury: Microthrombi and fibrocellular proliferation occlude the pulmonary microcirculation, causing pulmonary hypertension and increasing dead space.

The injured alveolus: multiple convergent pathways (neutrophils, monocytes, platelets, RBCs, mitochondrial dysfunction) disrupt the epithelial and endothelial barriers, flooding alveoli with edema and impairing fluid clearance. - Harrison's Principles of Internal Medicine 22E

Physiological consequences of the exudative phase

• Refractory hypoxemia: Large right-to-left intrapulmonary shunt forms because flooded/collapsed alveoli are still perfused. Mixed venous blood passes through these units without being oxygenated. Crucially, this shunt does not respond to supplemental oxygen alone - the hallmark of ARDS.
• Increased dead space: Microvascular occlusion reduces blood flow to ventilated lung units, causing hypercapnia and elevated minute ventilation requirements.
• Reduced lung compliance: The heavy, edematous, atelectatic lung (behaves like a sponge, with gravity-dependent consolidation) becomes stiff, increasing the work of breathing and leading to respiratory fatigue.
• Pulmonary hypertension: Results from hypoxic pulmonary vasoconstriction plus microvascular occlusion by microthrombi.

• Harrison's Principles of Internal Medicine 22E, pp. 2343-2344
• Fishman's Pulmonary Diseases and Disorders, pp. 2494-2495

Phase 2: Proliferative Phase (Days 7-21)

• Type II pneumocyte proliferation along alveolar basement membranes begins repair - these cells synthesize new surfactant and differentiate into type I pneumocytes.
• A shift from neutrophil- to lymphocyte-predominant infiltrate occurs.
• Alveolar exudates start to organize.
• Fibroblast and myofibroblast proliferation begins, with early interstitial fibrosis in some patients.
• Dead space fraction and pulmonary hypertension may worsen as fibroproliferation remodels the vasculature.

• Harrison's, p. 2344; Fishman's, p. 2495

Phase 3: Fibrotic Phase (Day 21 onwards - subset of patients)

• Alveolar edema and inflammatory exudate convert to alveolar-duct and interstitial fibrosis.
• Acinar architecture is destroyed, producing emphysema-like bullae.
• Intimal fibroproliferation in the pulmonary microcirculation causes progressive vascular occlusion and worsening pulmonary hypertension.
• Physiological consequences: further reduced compliance, increased dead space, risk of pneumothorax, and oxygen dependency.
• Lung biopsy evidence of fibrosis in any ARDS phase is associated with increased mortality.
• Harrison's, p. 2344-2345

Phase timeline summary

Time course of ARDS: edema and hyaline membrane formation dominate the first 7 days; interstitial inflammation characterizes days 7-14; fibrosis emerges beyond day 21. - Fishman's Pulmonary Diseases and Disorders

Key Pathophysiological Summary

• Harrison's Principles of Internal Medicine 22E, p. 2343
• Fishman's Pulmonary Diseases and Disorders, pp. 2494-2495
• Sabiston Textbook of Surgery, p. 940