Pulmonary deposition and clearance of aerosolized alpha-1-proteinase inhibitor administered to dogs and to sheep.
Augmentation of lung antiprotease levels may be an important therapeutic intervention in the prevention of pulmonary emphysema. We have administered aerosols of plasma-derived human alpha 1 proteinase inhibitor (A1PI) to the lungs of dogs and sheep to investigate (a) delivery of the protein to the distal air spaces of the lung; (b) maintenance of functional activity of the protein; and (c) flux of the protein across the components of the alveolar-capillary membrane. A1PI (26.4 mg/kg body weight) was administered as an aerosol to anesthetized animals; sheep were prepared for the chronic collection of lung lymph. Immunoperoxidase staining of lung tissue obtained 2 h after administration of A1PI demonstrated the presence of human A1PI on the surface of alveoli and distal bronchioles. Bronchoalveolar lavage fluid recovered at intervals after A1PI administration demonstrated time-dependent elevations of human A1PI levels with augmentation of lavage fluid antielastase activity in proportion to the content of human A1PI. Using radiolabeled A1PI as a tracer, we found that 32% of the aerosol was retained in the animals' lungs. Measurements of the rate of loss of A1PI from the lung and of the rate of appearance of human A1PI in plasma resulted in a calculated permeability of the alveolar-capillary membrane to A1PI of 3.49-6.39 X 10(-10) cm/s. Experiments using instrumented sheep allowed independent calculation of endothelial permeability to A1PI of 122-236 X 10(-10) cm/s and calculation of epithelial permeability of 4.70-4.81 X 10(-10) cm/s. Modeling of aerosol delivery of A1PI to humans using the results of these studies predicts that the ratio of plasma/alveolar levels of delivered A1PI will be 0.024, and that aerosolization of 175 mg A1PI/d will result in an A1PI alveolar fluid level of 1.0 mg/ml. Aerosol administration of A1PI may provide an efficient method of augmenting alveolar antiprotease levels.
Smith
R M
RM
Department of Medicine, University of California, San Diego 92103.
Traber
L D
LD
Traber
D L
DL
Spragg
R G
RG
D000336:Aerosols; D000818:Animals; D001345:Autoradiography; D001992:Bronchoalveolar Lavage Fluid / Q000032:analysis / Q000201:enzymology; D002199:Capillary Permeability; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism*; D008196:Lymph / Q000032:analysis; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011650:Pulmonary Alveoli / Q000098:blood supply; D012756:Sheep; D000515:alpha 1-Antitrypsin / Q000493:pharmacokinetics*
D000336:Aerosols; D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase