Replacement therapy of alpha 1-antitrypsin deficiency. Reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects

The emphysema associated with the inherited serum deficiency of α1-antitrypsin appears to result from an imbalance between neutrophil elastase and its major inhibitor within the alveolar structures. In the present study we assessed the feasibility of reversing this biochemical defect within the lung via parenteral replacement therapy with an α1-antitrypsin concentrate of normal plasma. A 20-40% polyethylene glycol precipitate of pooled human donor plasma was used to obtain an enriched α1-antitrypsin concentrate devoid of hepatitis B antigen and immunoglobulin. Using this material, five individuals with severe serum α1-antitrypsin deficiency (PiZ phenotype) and advanced emphysema received 4 g of α1-antitrypsin intravenously at weekly intervals for four doses. During this period of weekly replacement therapy α1-antitrypsin serum levels were maintained at ≥70 mg/dl, the level likely required for effective antielastase protection of the lung. In addition, assessment of lower respiratory tract antielastase activity by bronchoalveolar lavage demonstrated that parenteral replacement of α1-antitrypsin resulted in establishment of effective anti-elastase activity within the alveolar stuctures. There were no untoward side effects consequent to this approach to the replacement therapy of α1-antitrypsin. These results demonstrate that the parenteral replacement of α1-antitrypsin provides a means of obtaining elastase-antielastase balance within the lung of individuals with this serum protease inhibited deficiency.