Anti-neutrophil-elastase defenses of the lower respiratory tract in alpha 1-antitrypsin deficiency directly augmented with an aerosol of alpha 1-antitrypsin.
OBJECTIVE
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.


METHODS
Nonrandomized, before-and-after trial with a 7-day treatment period. Companion studies in animals to determine lung epithelial permeability to alpha 1-antitrypsin.


METHODS
Twelve patients with homozygous Z-type alpha 1-antitrypsin deficiency and mild to moderate emphysema.


METHODS
Aerosol administration of human plasma alpha 1-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.


RESULTS
Treatment resulted in increased alpha 1-antitrypsin levels in the lung epithelial lining fluid (0.28 +/- 0.07 microM before therapy to 5.86 +/- 1.03 microM after therapy) and increased anti-neutrophil-elastase capacity (0.78 +/- 0.38 microM before therapy to 4.16 +/- 0.95 microM 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.


CONCLUSIONS
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.
Hubbard
R C
RC
National Heart, Lung, and Blood Institute, Bethesda, Maryland.
Brantly
M L
ML
Sellers
S E
SE
Mitchell
M E
ME
Crystal
R G
RG
D000336:Aerosols; D000818:Animals; D006801:Humans; D008168:Lung / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D010539:Permeability; D011650:Pulmonary Alveoli / Q000378:metabolism; D012756:Sheep; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019896:alpha 1-Antitrypsin Deficiency
D000336:Aerosols; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase