Aerosolization of superoxide dismutase. Augmentation of respiratory epithelial lining fluid antioxidant screen by aerosolization of recombinant human Cu++/Zn++ superoxide dismutase.
Various human pulmonary diseases are characterized by an increased oxidant burden on the respiratory epithelial surface. As a step toward developing a therapy to augment the antioxidant defenses of respiratory epithelial lining fluid (ELF) of the human lung, we have evaluated the feasibility of aerosolizing a human protein antioxidant to the respiratory epithelial surface of an experimental animal sufficiently large to permit repetitive sampling of ELF. To accomplish this, recombinant human Cu++/Zn++ superoxide dismutase (rSOD) was aerosolized to sheep, and the levels of human superoxide dismutase (SOD) and antisuperoxide anion (O2.-) capacity were quantified in ELF over time. In vitro aerosolization did not alter the specific activity of rSOD (p > 0.5). In vivo aerosolization of rSOD (100 mg) to sheep (n = 7) resulted in peak amounts of human Cu++/Zn++ SOD in ELF of 3.1 +/- 0.6 mumol/L, with a parallel increase in the anti-O2.- capacity of ELF. For the duration of the study (5 h), levels of SOD and anti-O2.- in ELF remained elevated, with a value 50 percent of the peak at 5 h. Aerosolization of phosphate-buffered saline (n = 5) had no effect on SOD or anti-O2.- levels in ELF. In animals receiving rSOD, there was no change in the specific activity of SOD recovered in ELF compared to the starting material (p > 0.4). We conclude that rSOD can be delivered by aerosol to the ELF of a large animal with preservation of specific activity and that a substantial increase in both the amount of SOD and the anti-O2.- capacity can be achieved for a period of time applicable to human therapy, supporting the rationale for evaluation of rSOD aerosol as an antioxidant in human pulmonary disease.
Gillissen
A
A
Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Roum
J H
JH
Hoyt
R F
RF
Crystal
R G
RG
D000336:Aerosols; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D011994:Recombinant Proteins / Q000008:administration & dosage; D012137:Respiratory System / Q000378:metabolism*; D012756:Sheep; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000336:Aerosols; D000975:Antioxidants; D011994:Recombinant Proteins; D013481:Superoxides; D013482:Superoxide Dismutase