Anti-Neutrophil-Elastase Defenses of the Lower Respiratory Tract in α1-Antitrypsin Deficiency Directly Augmented with an Aerosol of α1-Antitrypsin

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Abstract
The study objective was to determine if aerosolization of purified human plasma .alpha.1-antitrypsin is an effective means for increasing lower respiratory anti-neutrophil-elastase defenses in .alpha.1-antitrypsin deficiency. The design was nonrandomized, before-and-after trial with a 7-day treatment period. Companion studies in animals to determine lung epithelial permeability to .alpha.1-antitrypsin. Twelve patients with homozygous Z-type .alpha.1-antitrypsin deficiency and mild to moderate emphysema were used in the study. Aerosol administration of human plasma .alpha.1-antitrypsin was used, 100 mg every 12 hours for 7 days. Single, 100-mg aerosol dose to anesthetized sheep with indwelling thoracic lymph duct catheters was used for direct assessment of lung permeability. Treatment resulted in increased .alpha.1-antitrypsin levels in the lung epithelial lining fluid (0.28 .+-. 0.07 .mu.M before therapy to 5.86 .+-. 1.03 .mu.M after therapy) and increased anti-neutrophil-elastase capacity (0.78 .+-. 0.38 .mu.M before therapy to 4.16 .+-. 0.95 .mu.M after therapy). Aerosolized .alpha.1-antitrypsin diffused across the respiratory epithelium and entered lung interstitial lymph (in sheep) and reached the systemic circulation (in sheep and humans). No side effects were noted. Short-term aerosol administration of human plasma .alpha.1-antitrypsin to patients with .alpha.1-antitrypsin deficiency is safe and feasible, resulting in a return to normal of anti-neutrophil-elastase defenses in the lower respiratory tract. The aerosol approach, therefore, merits serious long-term evaluation as an alternative to other parenteral forms of administering therapeutic proteins.

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