ISSN:
1432-1440
Keywords:
Key words α1-Antitrypsin
;
Lung
;
Surfactant protein C promoter
;
Clara cell protein 10 promoter
;
Haptoglobin promoter
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract α1-Antitrypsin (α1AT) therapy is used as a treatment for α1AT deficiency. It has also been proposed as a therapy for cigarette smoke-induced emphysema, although the efficacy of such therapy is as yet unproven. Moreover, the optimal route of delivery of α1AT to the lung interstitium, the crucial locus of action, is unknown. We created transgenic mice with expression of the human α1AT gene directed by a human surfactant protein C (SpC) promoter fragment or a rat Clara cell 10-kDa protein (CC10) promoter fragment in order to examine the ability of pulmonary epithelial cell expression of α1AT to deliver protein to the interstitium, and to produce a model that would allow studies on the efficacy of α1AT in preventing lung damage after cigarette smoke exposure. Four transgenic lines were studied. In situ hybridization and light microscopic immunohistochemistry showed that two CC10 driven lines expressed human α1AT in type II alveolar cells and airway epithelial cells; α1AT expression was seen in the alveolar parenchyma in two SpC driven lines, and in small airway epithelium in one of the SpC lines. Electron microscopic immunochemistry showed the presence of the human α1AT protein in the interstitium in all lines. Mean levels of human protein varied from 0.37 to 2.9 µg/g lung protein and serum levels from 0.72 to 1.3 µg/ml, compared to normal human serum α1AT levels of 2–5 mg/ml. We conclude that transgene-mediated expression of α1AT in pulmonary epithelial cells results in diffuse expression of the transgene in the alveolar parenchyma and reproducibly leads to transfer of protein to the interstitium. The present model is, however, limited by low levels of protein production; limited protein production may be a problem in other forms of gene therapy in which relatively large amounts of extracellular protein are needed in the lung for a therapeutic effect.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s001090050364
Permalink
