Etiology

Emphysema is caused by chronic destruction of alveolar walls due to an imbalance between proteases and antiproteases, most commonly triggered by long‑term exposure to inhaled irritants—especially cigarette smoke.

1. Cigarette smoking — #1 cause

Smoking is responsible for the vast majority of emphysema cases.
Cigarette smoke increases neutrophil and macrophage recruitment → ↑ elastase and other proteases → destruction of alveolar septa and loss of elastic recoil.
Smoke also inactivates α1‑antitrypsin, worsening protease‑mediated injury.

2. Environmental & Occupational Exposures

Chronic inhalation of irritants can independently cause emphysema or synergize with smoking:

Chemical fumes
Dusts (grain, cotton, wood, mining)
Vapors and air pollutants (indoor & outdoor)
These exposures promote chronic inflammation and protease release.

3. Alpha‑1 Antitrypsin Deficiency (AATD) — genetic cause

Accounts for a small but important subset of emphysema cases.
Caused by mutations in SERPINA1, most commonly the Z allele, leading to low functional AAT levels.
Without AAT, neutrophil elastase is unopposed → panacinar emphysema, especially in lower lobes.
Smoking accelerates disease dramatically.

4. Other Contributors

Recurrent respiratory infections (inflammatory burden)
Marijuana smoke, vaping aerosols, and cigar smoke (similar irritant effects)
Genetic susceptibility beyond AATD (inferred from variable smoker risk)

Summary

Across all causes, emphysema results from:

Excess protease activity (neutrophil elastase, MMPs)
Insufficient antiprotease protection (AAT deficiency or smoke‑mediated inactivation)
Oxidative stress from smoke or pollutants

Summary

Emphysema = chronic protease‑mediated alveolar destruction.

Smoking is the dominant cause.
AAT deficiency is the key genetic cause.
Environmental irritants and inflammation accelerate damage.