What is the pathophysiology of Acute Respiratory Distress Syndrome (ARDS)?

Pathophysiology of Acute Respiratory Distress Syndrome (ARDS)

ARDS is characterized by leukocyte infiltration, local immune activation, alveolar endothelial and epithelial injury, increased pulmonary vascular permeability, acute pulmonary edema, and loss of aerated lung tissue, resulting in severe hypoxemia and respiratory failure. 1

Primary Pathophysiological Mechanisms

Alveolar-Capillary Barrier Disruption

• Endothelial Injury: Occurs within minutes to hours after lung injury, creating intercellular gaps that allow fluid, neutrophils, and cytokines to enter the pulmonary parenchyma 1
• Epithelial Damage: Disruption of tight junctions between alveolar epithelial cells allows protein-rich fluid to flood alveolar spaces 1
• Basement Membrane Disruption: Electron microscopy reveals denudation of alveolar epithelial cells and basement membrane damage 1

Inflammatory Response

• Neutrophil Activation: Bronchoalveolar lavage fluid from ARDS patients contains increased quantities of neutrophils and their enzymes, correlating with injury severity 1
• Cytokine Storm: Persistent plasma elevations of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8) correlate with reduced survival 1
• Anti-inflammatory Imbalance: Increased bronchoalveolar lavage fluid anti-inflammatory cytokines like IL-10 correlate with improved survival 1

Oxidative Stress

• Reactive Oxygen Species: Neutrophils and alveolar macrophages produce inflammatory mediators and catalyze reactive oxygen species generation 1
• Lipid Peroxidation: Evidence of lipid peroxidation products correlates with disease severity and survival 1
• Antioxidant Depletion: Plasma thiol levels correlate with survival in ARDS patients 1

Surfactant Dysfunction

• Surfactant depletion and inactivation occurs due to protein-rich edema fluid 1
• Results in alveolar collapse, decreased lung compliance, and impaired gas exchange 1

Pathophysiological Progression

Early Exudative Phase (Days 1-5)

• Interstitial swelling, proteinaceous alveolar edema, hemorrhage, and fibrin deposition 1
• Hyaline membrane formation (sloughed alveolar cellular debris mixed with fibrin) 1
• Extensive right-to-left intrapulmonary shunting causing severe hypoxemia 1
• Decreased lung compliance due to reduced volume of aeratable lung 1

Fibroproliferative Phase (Days 6-10)

• Type II alveolar cells proliferate and differentiate into new type I cells to reline alveolar walls 1
• Alveolar edema begins to resolve and hyaline membranes become less prominent 1
• Neutrophilic infiltrate is replaced by mononuclear cells 1
• Fibroblasts proliferate within the interstitium and deposit new collagen 1

Fibrotic Phase (After 10 Days)

• Pulmonary fibrosis develops with widened interstitial structures 1
• Pulmonary hypertension may worsen due to vascular bed obliteration 1
• Changes may not resolve for months or may result in chronic fibrotic changes 1

Heterogeneity in ARDS Pathophysiology

ARDS demonstrates significant heterogeneity on three distinct levels 1:

1. Aetiological Heterogeneity:

   • Multiple triggering factors (sepsis, pneumonia, trauma, blood transfusion, pancreatitis)
   • Different risk factors affect inflammatory response patterns

2. Physiological Heterogeneity:

   • Variable degrees of lung compliance and recruitability
   • Differences in ventilation-perfusion matching
   • Varying responses to PEEP and recruitment maneuvers

3. Biological Heterogeneity:

   • Hyperinflammatory vs. hypoinflammatory phenotypes with different biomarker profiles
   • Variable gene expression patterns in peripheral blood leukocytes
   • Different responses to pharmacological interventions

Clinical Implications

• The complex pathophysiology explains why targeted pharmacological treatments have largely failed in unselected ARDS populations 1
• Precision medicine approaches that account for ARDS heterogeneity may be necessary for successful therapeutic interventions 1
• Lung-protective ventilation strategies remain the cornerstone of management, focusing on preventing ventilator-induced lung injury 2
• Mortality remains high (30-40%) despite advances in supportive care 1

Key Pitfalls in Understanding ARDS Pathophysiology

• Diagnostic Confusion: Current definitions are inclusive, potentially grouping patients with heterogeneous conditions 1
• Treatment Misdirection: Targeting a single pathway may not benefit all patients due to biological heterogeneity 1
• Prognostic Limitations: Initial hypoxemia severity is not a reliable prognostic indicator, though changes in oxygenation over the first 48 hours appear more predictive 1

Understanding the complex pathophysiology of ARDS is essential for developing effective therapeutic strategies that account for the syndrome's heterogeneity and target specific pathobiological mechanisms.