Strategies for aerosol therapy of α1-antitrypsin deficiency by the aerosol route

Richard C. Hubbard, Ronald Crystal

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

α 1-antitrypsin (AAT) deficiency is a genetic disease in which low serum and lung levels of the antiprotease AAT cause a deficiency of the anti-elastase defensive screen of the lower respiratory tract such that neutrophil elastase is free to degrade the connective tissue of the lung, eventually resulting in emphysema. Intravenous AAT infusion therapy restores lung levels of AAT, but is inefficient, costly and a demanding form of therapy. As an alternative, we evaluated aerosol delivery of human plasma AAT (pAAT) and recombinant DNA-produced AAT (rAAT), as a means of providing anti-elastase protection to the lower respiratory tract. In vitro studies demonstrated that both pAAT and rAAT can be aerosolized into droplets suitable for alveolar deposition without loss of antiprotease activity. When administered by aerosol to individuals with AAT deficiency, pAAT and rAAT each significantly raised lung epithelial lining fluid levels of AAT and anti-neutrophil elastase capacity, with the likelihood that twice daily administration of 100 mg of either form would result in normalization of lung anti-elastase defenses at the alveolar surface. Studies in sheep further demonstrated that the aerosolized pAAT and rAAT were each able to pass through alveolar epithelium and gain access to the interstitial compartment of the lung, thus increasing anti-elastase defenses of the lung intersitium. Therapy was safe and well tolerated in all cases. Aerosol therapy with pAAT or rAAT is a safe, feasible, and likely a biochemically efficacious alternative to intravenous AAT augmentation therapy and merits further long-term studies for clinical therapy.

Original languageEnglish
Pages (from-to)565-578
Number of pages14
JournalLung
Volume168
Issue number1
DOIs
Publication statusPublished - 1 Jan 1990
Externally publishedYes

Fingerprint

Aerosols
Recombinant DNA
Pancreatic Elastase
Lung
Leukocyte Elastase
Protease Inhibitors
Respiratory System
Therapeutics
Inborn Genetic Diseases
Emphysema
Intravenous Infusions
Connective Tissue
Sheep
Epithelium
Serum

Keywords

  • Antiprotease
  • elastase
  • Emphysema
  • Lung
  • Nebulizer
  • Neutrophil

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Strategies for aerosol therapy of α1-antitrypsin deficiency by the aerosol route. / Hubbard, Richard C.; Crystal, Ronald.

In: Lung, Vol. 168, No. 1, 01.01.1990, p. 565-578.

Research output: Contribution to journalArticle

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