IN-VIVO ADENOVIRUS-MEDIATED GENE-TRANSFER VIA THE PULMONARY-ARTERY OF RATS

被引:44
作者
SCHACHTNER, SK
ROME, JJ
HOYT, RF
NEWMAN, KD
VIRMANI, R
DICHEK, DA
机构
[1] ARMED FORCES INST PATHOL, CARDIOVASC SECT, WASHINGTON, DC 20306 USA
[2] NHLBI, MOLEC HEMATOL BRANCH, BETHESDA, MD 20892 USA
[3] NHLBI, ANIM MED & SURG LAB, BETHESDA, MD 20892 USA
[4] CHILDRENS NATL MED CTR, DEPT CARDIOL, WASHINGTON, DC 20010 USA
[5] CHILDRENS NATL MED CTR, DEPT SURG, WASHINGTON, DC 20010 USA
关键词
PULMONARY ARTERY; PULMONARY HYPERTENSION; GENE TRANSFER; GENE THERAPY; ADENOVIRUS;
D O I
10.1161/01.RES.76.5.701
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Gene transfer into the pulmonary vasculature has the potential to be a powerful technique for both investigation of pulmonary pathophysiology and development of genetic therapies for pulmonary vascular disease. To evaluate the potential for in vivo pulmonary arterial gene transfer, we infused adenoviral vectors into the left pulmonary artery of Sprague-Dawley and cotton rats. Access to the left pulmonary artery was obtained by a percutaneous transcatheter approach or through thoracotomy and pulmonary arteriotomy. With the thoracotomy approach, both pulmonary arterial inflow and pulmonary venous outflow were occluded during vector infusion and throughout a subsequent 20-minute dwell period. The success of gene transfer was assessed by staining for evidence of recombinant gene expression in lungs excised at lime points ranging from 48 to 72 hours after virus infusion. With the thoracotomy technique, pulmonary gene transfer was successful in 15% of surviving Sprague-Dawley rats and 30% of surviving cotton rats. Percutaneous catheter-based pulmonary gene transfer was not successful. In rats with pulmonary gene transfer, 1% to 8% of total left lung cells expressed the recombinant gene. Recombinant gene expression was found in endothelial cells (0.2% to 18% of total transduced cells), smooth muscle cells (0% to 3%), macrophages (1% to 7%), airway epithelial cells (2% to 50%), and alveolar epithelial cells (38% to 94%). Investigation of the low rate of successful gene transfer in individual animals suggested that insufficient physical contact between the virions and pulmonary cells was the most likely cause. In vivo gene transfer into the rat pulmonary vasculature can be accomplished with adenovirus vectors. The overall efficiency is low, however, and pulmonary arterial infusion of the vectors results in gene transfer primarily into nonvascular cells.
引用
收藏
页码:701 / 709
页数:9
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