Therapeutic elastase inhibition by alpha-1-antitrypsin gene transfer limits neointima formation in normal rabbits

PURPOSE: Alpha-l-antitrypsin (AAT) is the major circulating elastase inhibi tor. Deficiency of elastase inhibition leads to emphysema and vascular abno rmalities including accelerated neointima. Because recent evidence suggests that tissue AAT levels determine inhibitory function, the authors hypothes ize that local tissue-based expression of AAT limits elastase activity suff iciently to guide arterial response to injury. MATERIALS AND METHODS: Rabbit common femoral arteries were injured by mecha nical overdilation and treated with buffer, viral control, or an adenovirus expressing AAT (Ad/AAT). After 3 and 28 days, intima-to-media (I/M) ratios were evaluated. Additionally, early changes in elastase inhibition potenti al (3 d), extracellular elastin and collagen content (3 d), and local macro phage and neutrophil infiltration (7 d) were determined. RESULTS: Ad/AAT significantly decreased neointima formation after mechanica l dilation injury after 28 days: buffer controls exhibited mean I/M ratios of 0.76 +/- 0.06, whereas viral controls reached 0.77 +/- 0.09; in contrast , Ad/AAT reduced I/M ratios to 0.44 +/- 0.06. Both early elastin and collag en content were preserved in the Ad/AAT group relative to controls. The Ad/ AAT group also reversed the local inflammation that characterized viral con trols. CONCLUSIONS: This strategy demonstrates that local increases in elastase in hibition potential promote a neointima-resistant small-caliber artery, whic h may offer new promise in management of patients undergoing angioplasty.