Intrapleural adenoviral delivery of human plasminogen activator inhibitor-1 exacerbates tetracycline-induced pleural injury in rabbits.

Am J Respir Cell Mol Biol 2013 Jan 20;48(1):44-52. Epub 2012 Sep 20.

Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.

Elevated concentrations of plasminogen activator inhibitor-1 (PAI-1) are associated with pleural injury, but its effects on pleural organization remain unclear. A method of adenovirus-mediated delivery of genes of interest (expressed under a cytomegalovirus promoter) to rabbit pleura was developed and used with lacZ and human (h) PAI-1. Histology, β-galactosidase staining, Western blotting, enzymatic and immunohistochemical analyses of pleural fluids (PFs), lavages, and pleural mesothelial cells were used to evaluate the efficiency and effects of transduction. Transduction was selective and limited to the pleural mesothelial monolayer. The intrapleural expression of both genes was transient, with their peak expression at 4 to 5 days. On Day 5, hPAI-1 (40-80 and 200-400 nM of active and total hPAI-1 in lavages, respectively) caused no overt pleural injury, effusions, or fibrosis. The adenovirus-mediated delivery of hPAI-1 with subsequent tetracycline-induced pleural injury resulted in a significant exacerbation of the pleural fibrosis observed on Day 5 (P = 0.029 and P = 0.021 versus vehicle and adenoviral control samples, respectively). Intrapleural fibrinolytic therapy (IPFT) with plasminogen activators was effective in both animals overexpressing hPAI-1 and control animals with tetracycline injury alone. An increase in intrapleural active PAI-1 (from 10-15 nM in control animals to 20-40 nM in hPAI-1-overexpressing animals) resulted in the increased formation of PAI-1/plasminogen activator complexes in vivo. The decrease in intrapleural plasminogen-activating activity observed at 10 to 40 minutes after IPFT correlates linearly with the initial concentration of active PAI-1. Therefore, active PAI-1 in PFs affects the outcome of IPFT, and may be both a biomarker of pleural injury and a molecular target for its treatment.

Download full-text PDF

Source
http://www.atsjournals.org/doi/abs/10.1165/rcmb.2012-0183OC
Publisher Site
http://dx.doi.org/10.1165/rcmb.2012-0183OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547083PMC
January 2013

Publication Analysis

Top Keywords

pleural injury
20
active pai-1
12
pleural
10
control animals
8
plasminogen activator
8
activator inhibitor-1
8
tetracycline-induced pleural
8
pleural mesothelial
8
adenovirus-mediated delivery
8
injury
6
pai-1
5
intrapleural
5
vivo decrease
4
expression genes
4
genes transient
4
peak expression
4
animals
4
transient peak
4
days day
4
activators effective
4

Similar Publications