Parker B. Francis Lectureship. Antitrypsin Deficiency, the Serpinopathies, and Chronic Obstructive Pulmonary Disease

alpha(1)-Antitrypsin deficiency is the only genetic factor that is widely recognized to predispose smokers to chronic obstructive pulmonary disease. We have shown that the plasma deficiency results from point mutations perturbing the structure of the protein to favor sequential linkage between the reactive center loop of one molecule and beta-sheet A of another. These polymers are retained within the liver to form the periodic acid-Schiff-positive inclusions that are characteristic of the disease. Intracellular polymerization also explains the retention of mutants of other members of the serine proteinase inhibitor (or serpin) superfamily to cause diseases as diverse as thrombosis, angio-edema, and dementia. In view of the common mechanism, we have grouped these conditions together as the serpinopathies. Intrapulmonary Z alpha(1)-antitrypsin similarly forms polymers within the alveolar space. These polymers are inactive as a proteinase inhibitor and act as a chemoattractant for neutrophils. This conformational transition may explain the excessive inflammation that underlies the progressive emphysema associated with Z alpha(1)-antitrypsin deficiency.