Alpha1-Antitrypsin Deficiency in COPD: Clinical Implications

Elastase and Anti-elastase Balance in the Normal Lung

Control of elastase-mediated degradation of elastic tissue in the lung requires both an optimal concentration and function of anti-elastase. This balance (Table I) is maintained by a protective "screen" of alpha₁-AT (the major anti-elastase) in the lower respiratory tract at a functional concentration of about 1.3 mcM or more.^[7]

The destructive changes of emphysema generally occur at the lung bases (Fig. 2) where, because of gravity-related effects on blood flow, the neutrophil elastase burden may be greater. Under normal conditions, there is a sufficient concentration of functional alpha₁-AT to "bind up" free neutrophil elastase and the balance maintains elastic tissue integrity. Anti-elastase activity, as measured in bronchoalveolar lavage is significantly reduced in the lower respiratory tract in cases of alpha₁-ATD.^[7,8] In addition urinary elastin-specific crosslinks desmosine and isodesmosine -- the breakdown signature of mature elastin -- levels are elevated in patients with alpha₁-ATD. This finding suggests that without the normal anti-elastase constraint, elastin breakdown occurs at a greater rate.^[9]

Figure 2. Typical chest radiograph of a patient with alpha ₁-ATD related-emphysema. The posterior-anterior film of this 38-year-old woman (left) shows hyperinflation of the lung fields which predominates in the lower zones; the site where protease burden is thought to be greatest. Lateral film (right) shows extreme hyperinflation leading to inversion of the diaphragm.

Certain acquired conditions (Table I), also lead to a decrease in the anti-neutrophil elastase activity of alpha₁-AT. An example of this relative deficiency is the oxidation of the elastase combination site by cigarette smoke.^[10] This event reduces the alpha₁-AT association rate constant 2000-fold and increases its tendency to dissociate from neutrophil elastase. During inflammatory conditions of the lung, oxidation of alpha₁-AT occurs as a result of the reaction with hydrogen peroxide and myeloperoxidase released by activated neutrophils and alveolar macrophages.^[11,12] Through a variety of mechanisms -- including oxidation of alpha₁, increased binding of alpha₁, and massive influx of neutrophils during pulmonary inflammation, eg, pneumonia, ARDS -- inflammatory conditions of the lung shift the elastase anti-elastase balance in favor of elastin breakdown.

Cite this: Alpha1-Antitrypsin Deficiency in COPD: Clinical Implications - Medscape - Mar 01, 1998.