What is the pathophysiology of emphysema?

Pathophysiology of Emphysema

Emphysema is defined anatomically as a permanent destructive enlargement of airspaces distal to the terminal bronchioles, without obvious fibrosis, leading to decreased lung function and impaired gas exchange. 1 This destruction results in loss of elastic recoil, alveolar attachments, and airspace enlargement, which ultimately causes ventilation-perfusion mismatch and contributes to hypoxemia.

Structural Changes

Lung Parenchyma Destruction

• Permanent destruction of alveolar walls leads to airspace enlargement
• Loss of elastic recoil in lung tissue
• Decreased surface area for gas exchange
• Lung hyperexpansion and increased work of breathing 2

Patterns of Emphysema

Several distinct patterns of emphysema exist, each with different pathological features:

1. Centriacinar (Centrilobular) Emphysema:

   • Primarily affects respiratory bronchioles, alveolar ducts, and alveoli at the center of the acinus
   • Surrounding alveoli remain intact
   • Most commonly associated with cigarette smoking
   • Characterized by more small airways disease and less loss of elastic recoil 1

2. Panacinar Emphysema:

   • Involves destruction of the entire acinus
   • Results in earlier loss of lung recoil
   • Often associated with alpha-1 antitrypsin deficiency 1

3. Paraseptal Emphysema:

   • Affects areas adjacent to the connective tissue septa
   • Strongly associated with lung scarring in COPD
   • Characterized by subpleural bullae adjacent to areas of fibrosis 1

Pathogenic Mechanisms

Protease-Antiprotease Imbalance

The most accepted hypothesis for emphysema development involves an imbalance between proteases and antiproteases:

• Alpha-1-antitrypsin is the major antielastase of the normal human lower respiratory tract 3
• In alpha-1-antitrypsin deficiency, there is little or no protection against neutrophil elastase in the lower respiratory tract 3
• Neutrophil elastase is a potent elastolytic enzyme that can degrade elastin within the fiber network of the extracellular matrix 4
• Alveolar macrophages express elastolytic enzymes (cathepsins and matrix metalloproteases) that are induced by smoking 4
• Macrophage numbers increase in the respiratory bronchiole region, where centrilobular emphysema typically develops 4

Mechanical Forces and Collagen Failure

Recent evidence suggests additional mechanisms:

• Mechanical forces during breathing can cause failure of the remodeled extracellular matrix at stress concentration points 2
• In elastase-treated tissue, significant remodeling leads to thickened elastin and collagen fibers
• These remodeled fibers undergo larger distortions during stretching than in normal tissue
• The threshold for mechanical failure of collagen, which provides mechanical stability to the normal lung, is reduced 2

Other Pathogenic Mechanisms

Additional mechanisms contributing to emphysema include:

• Oxidative stress
• Cell apoptosis
• Cellular senescence
• Failed lung tissue repair 5

Functional Consequences

Airflow Limitation

• Loss of lung recoil appears early in panacinar emphysema development
• In severe COPD, emphysema is considered the most important factor in airflow limitation
• In mild to moderate COPD, small airway changes play a greater role 6

Gas Exchange Impairment

• Ventilation-perfusion (V'/Q') inequality is the major mechanism impairing gas exchange and leading to arterial hypoxemia at all stages of COPD
• As emphysema progresses, lung elastic recoil and carbon monoxide transfer coefficient decrease
• Static lung compliance and total lung capacity increase 6

Hyperinflation and Respiratory Mechanics

• Hyperinflation and intrinsic PEEP from dynamic hyperinflation lead to:
  • Increased functional residual capacity
  • Flattened diaphragm
  • Increased work of breathing 1

Clinical Implications

• Understanding the type of emphysema is crucial for:

  • Predicting disease progression
  • Assessing risk of complications
  • Determining appropriate management strategies
  • Evaluating prognosis 1

• CT scanning is the gold standard for identifying emphysema subtypes, with paraseptal emphysema having a characteristic appearance with subpleural bullae adjacent to areas of fibrosis 1

Disease Evolution

As COPD progresses:

• FEV1 and vital capacity decrease
• Residual volume increases
• Rate of FEV1 decline is greater than in normal subjects
• Total airway resistance increases
• Ventilation-perfusion inequality worsens 6

In advanced COPD, additional changes occur in:

• Pulmonary circulation (medial vascular smooth muscle extends distally)
• Right heart (ventricular enlargement due to dilatation/hypertrophy)
• Respiratory muscles (diaphragm atrophy may occur) 6