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

Abstract

Study Objective: To determine if aerosolization of purified human plasma α1-antitrypsin is an effective means for increasing lower respiratory anti-neutrophil-elastase defenses in α1-antitrypsin deficiency.

Design: Nonrandomized, before-and-after trial with a 7-day treatment period. Companion studies in animals to determine lung epithelial permeability to α1-antitrypsin.

Patients: Twelve patients with homozygous Z-type α1-antitrypsin deficiency and mild to moderate emphysema.

Interventions: Aerosol administration of human plasma α1-antitrypsin, 100 mg every 12 hours for 7 days. Single, 100-mg aerosol dose to anesthetized sheep with indwelling thoracic lymph duct catheters for direct assessment of lung permeability.

Measurements and Main Results: Treatment resulted in increased α1-antitrypsin levels in the lung epithelial lining fluid (0.28 ±0.07 µM before therapy to 5.86 ±1.03 µM after therapy) and increased anti-neutrophil-elastase capacity (0.78 ±0.38 ΩM before therapy to 4.16 ±0.95 µM after therapy). Aerosolized α1-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.

Conclusion: Short-term aerosol administration of human plasma α1-antitrypsin to patients with α1-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 longterm evaluation as an alternative to other parenteral forms of administering therapeutic proteins.