Emphysema

Emphysema is defined in structural and pathological terms as:
‘A condition of the lung characterised by abnormal,permanent enlargement of the air spaces distal to the terminal bronchiole, accompanied by destruction of their walls.’

This definition describes a destructive process that is largely associated with cigarette smoking.Cigarette smoke is an irritant and results in low-grade inflammation of the airways and alveoli. Bronchoalveolar lavage of smokers’ lungs reveals increased numbers of inflammatory cells, notably macrophages and neutrophils. These inflammatory cells produce elastases – proteolytic enzymes that
destroy elastin, the protein that makes up lung tissue. In health, these enzymes are neutralised by anti-elastases, anti-proteolytic enzymes, the most widely studied of which is alpha-1 antitrypsin show the histology of normal lung tissue and of emphysema.

Alpha-1 antitrypsin deficiency accounts for 1–2% of all cases of diagnosed COPD. It provides a good model for our current understanding of the role of elastases and anti-elastases in the development of emphysema.

In early experiments, elastases introduced into lung tissue deficient in alpha-1 antitrypsin digested that lung tissue, thus producing emphysema.When alpha-1 antitrypsin was introduced into the deficient lung tissue – thereby effectively making it ‘normal’ – it protected against the action of the elastases and thus prevented emphysema.

That elastases are responsible for the destruction of lung tissue was confirmed by further experiments. A purified elastase was derived from neutrophils, a white blood cell attracted into the lungs of smokers. This neutrophil elastase (NE) was instilled into the lungs of experimental animals, causing a transient decrease in lung elastin, which then gradually returned to normal. However, although the loss of elastin was temporary, the structure of the animals’ lungs was permanently damaged.

The elastase/anti-elastase hypothesis for the development of emphysema in humans is that the irritant effect of cigarette smoke increases the level of elastases in the lungs beyond the body’s ability to neutralise them. Over many years lung elastin is lost, lung tissue is destroyed and emphysema results.

Although these and other experiments helped to explain the mechanisms behind the development of emphysema in people who are deficient in alpha-1 antitrypsin, it remains less clear what happens in people who are not deficient in this anti-proteolytic enzyme. There are several theories but further investigation is needed.
One theory is that, in some smokers, excessive numbers of inflammatory cells are attracted into the lungs in response to the irritant effects of cigarette smoke.These inflammatory cells, particularly neutrophils, are responsible for the release of elastases into the lung tissue; if too many are attracted into the lung, the amount of elastase they produce may outstrip the protective capacity of the
anti-elastases. It is thought that in some individuals the inflammatory cells themselves produce excessive amounts of elastases.

Yet another hypothesis is that there is excessive inactivation of the protective anti-elastases such that the individual is somewhat deficient in these protective enzymes. It is thought that this inactivation may be caused by oxidants that are both present in cigarette smoke and released from the activated inflammatory cells
present in the airways of smokers.

These hypotheses can be summarised as:

Abnormally high numbers of inflammatory cells are attracted into the airways,resulting in excessive production of elastases.

The inflammatory cells in the airways produce abnormally large amounts of elastases.

Oxidants found in cigarette smoke and released from inflammatory cells inactivate the protective anti-elastases in the lung.

In practice, all these mechanisms may be interacting in a single individual.Elastases, NE in particular, have been implicated in the development of chronic bronchitis as well as emphysema. They have been found to produce an increase in the number of goblet cells, a feature of chronic bronchitis. NE is also a potent inducer of mucus secretion, and causes a reduction of ciliary beat frequency.

Thus elastase/anti-elastase imbalance may be implicated not only in the development of emphysema but also in the pathogenesis of chronic bronchitis.