The current concepts of the pathogenesis of
emphysema hold that progressive, chronic destruction of the alveolar structures occurs because there was in imbalance between the
proteases and
antiproteases in the lower respiratory tract. In this context,
proteases, particularly
neutrophil elastase, work unimpeded to destroy the alveolar structures. This concept has evolved from consideration of patients with
alpha 1-antitrypsin deficiency, who have decreased levels of serum
alpha 1-antitrypsin and who have progressive
panacinar emphysema. To directly assess the
antiprotease side of this equation, the lower respiratory tract of non-smoking individuals with normal serum
antiproteases and individuals with PiZ homozygous
alpha 1-antitrypsin deficiency underwent bronchoalveolar lavage to evaluate the
antiprotease screen of their lower respiratory tract. These studies demonstrated that: (a)
alpha 1-antitrypsin is the major antielastase of the normal human lower respiratory tract; (b)
alpha 2-macroglobulin, a large serum antielastase, and the bronchial mucous inhibitor, an antielastase of the central airways, do not contribute to the antielastase protection of the human alveolar structures; (c) individuals with PiZ
alpha 1-antitrypsin deficiency have little or no
alpha 1-antitrypsin in their lower respiratory tract and have no alternative
antiprotease protection against
neutrophil elastase; and (d) the lack of
antiprotease protection of the lower respiratory tract of PiZ individuals is a chronic process, suggesting their vulnerability to
neutrophil elastase is always present.