What causes emphysema?

Causes of Emphysema

Cigarette smoking is the single most important cause of emphysema, leading to chronic inflammatory response and oxidative stress in the lungs that destroys alveolar walls and reduces elastic recoil. 1

Primary Causes

1. Cigarette Smoking

• Accounts for the vast majority of emphysema cases 1
• Risk increases proportionally with tobacco exposure (pack-years) 1
• Smoking cessation can slow disease progression but cannot reverse existing damage 1
• Mechanisms of lung damage from smoking:
  • Oxidative stress that inactivates alpha-1 antitrypsin (AAT) by converting active site Met358 to methionine sulfoxide 1
  • Recruitment of inflammatory cells, particularly neutrophils 1
  • Release of proteolytic enzymes that destroy lung tissue 1
  • Impairment of lung elastin resynthesis 1

2. Alpha-1 Antitrypsin Deficiency (AATD)

• Genetic disorder causing reduced levels of AAT, a protective enzyme that inhibits neutrophil elastase 1
• PI*ZZ phenotype is associated with severe deficiency and highest risk 1
• Even without smoking, AATD can cause emphysema, but smoking dramatically accelerates disease progression 1
• Serum levels below 11 μM (or approximately 50 mg/dl) are associated with increased risk 1

3. Environmental and Occupational Exposures

• Indoor air pollution (kerosene heating, biomass fuels) 1
• Occupational exposures to dusts, fumes, and gases 1
• Agricultural occupations 1
• Mining and grain working 1
• Urban living (air pollution) 1

Pathophysiological Mechanisms

1. Protease-Antiprotease Imbalance

• Neutrophil elastase and other proteases break down lung tissue 1, 2
• AAT normally inhibits these proteases, protecting lung tissue 1
• In smokers, the association rate constant (kₐₛₛₒc) of lung AAT for neutrophil elastase is reduced by approximately 20% 3
• This means it takes twice as long for neutrophil elastase to be inhibited in smokers' lungs 3

2. Oxidative Stress

• Cigarette smoke contains oxidants that damage lung tissue directly 1
• p-Benzoquinone (p-BQ) in cigarette smoke has been identified as a causative factor for alveolar cell destruction 4
• Oxidants inactivate AAT by oxidizing its active site, reducing its protective capacity 1, 3

3. Cellular and Molecular Mechanisms

• Apoptosis (programmed cell death) of alveolar cells 2
• Cellular senescence 2
• Impaired lung tissue repair 2
• Chronic inflammation 1
• Autophagy dysregulation 5

Risk Factors and Disease Progression

1. Genetic Factors

• AAT deficiency phenotypes (PIZZ, PISZ) 1
• Other genetic factors affecting susceptibility to smoke-induced damage 1
• Family history of COPD increases risk 1

2. Disease Progression

• FEV₁ decline in COPD averages about 70 ml per year (compared to 30 ml/year in normal aging) 1
• Smoking cessation slows the rate of decline to that of non-smokers 1
• Continued smoking accelerates decline, particularly when FEV₁ is between 30-65% of predicted 1

Preventive Measures

1. Smoking cessation - most effective intervention 1
2. Avoidance of occupational and environmental exposures 1
3. Vitamin C supplementation may help prevent p-BQ-induced damage 4
4. Early detection and management of AAT deficiency 1

Clinical Implications

• Emphysema leads to permanent destructive enlargement of airspaces, destruction of alveolar walls, and loss of elastic recoil 6
• Results in increased lung compliance, hyperinflation, and air trapping 6
• Characterized by increased total lung capacity (TLC), residual volume (RV), and reduced diffusing capacity (DLCO) 6
• Diaphragm flattening occurs in advanced disease, causing mechanical disadvantage of respiratory muscles 6

Understanding the causes and mechanisms of emphysema is crucial for developing effective prevention strategies and targeted treatments to slow disease progression and improve quality of life.