Pathogenesis

Only susceptible individuals develop emphysema but in most cases the factors governing susceptibility are poorly understood.

The alveolar wall destruction typical of emphysema may be explained by the protease-antiprotease theory. The pulmonary protease is elastase derived from neutrophils and macrophages; the principal anti-protease is alpha-1 antitrypsin.

The main elements of the theory are:

• tobacco smoke and other irritants result in inflammation and the influx of neutrophils and macrophages into the alveoli and bronchioles
• elastase is released which breaks down elastin fibres and other structural proteins
• serine protein inhibitors, principally alpha-1 antitrypsin, down-regulate the tissue destruction
• chronic inflammation eventually degrades alveolar walls
• protease overactivity is favoured by:
  • inactivation of alpha-1 antitrypsin by oxidants in smoke and oxygen free radicals secreted by neutrophils
  • hereditary deficiency in alpha-1 antitrypsin activity

Heavy smoking alone causes emphysema around the 6th decade.

Homozygotes for alpha-1 AT deficiency develop severe emphysema around the 4th decade. This is accelerated in smokers.

Weight loss, which is a common feature of the illness, and which is associated with increased morbidity and mortality, is thought to result from the release of TNF-alpha from hypoxic tissues.