Cell-based angiopoietin-1 gene therapy for acute lung injury.
BACKGROUND
The acute respiratory distress syndrome is a significant cause of morbidity and mortality in critically ill patients. Angiopoietin-1 (Ang-1), a ligand for the endothelial Tie2 receptor, is an endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions.


OBJECTIVE
We hypothesized that Ang-1 counteracts vascular inflammation and pulmonary vascular leak in experimental acute lung injury.


METHODS
We used cell-based gene therapy in a rat model of ALI. Transgenic mice overexpressing Ang-1 or deficient in the Tie2 receptor were also studied to better elucidate the mechanisms of protection.


RESULTS
The present report provides data that support a strong protective role for the Ang-1/Tie2 system in two experimental models of LPS-induced acute lung injury. In a rat model, cell-based Ang-1 gene transfer improved morphological, biochemical, and molecular indices of lung injury and inflammation. These findings were confirmed in a gain-of-function conditional, targeted transgenic mouse model, in which Ang-1 reduced endothelial cell activation and the expression of adhesion molecules, associated with a marked improvement in airspace inflammation and intraalveolar septal thickening. Moreover, heterozygous Tie2-deficient mice demonstrated enhanced evidence of lung injury and increased early mortality.


CONCLUSIONS
These results support a critical role for the Ang-1/Tie2 axis in modulating the pulmonary vascular response to lung injury and suggest that Ang-1 therapy may represent a potential new strategy for the treatment and/or prevention of acute respiratory distress syndrome in critically ill patients.
McCarter
Sarah D
SD
St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada.
Mei
Shirley H J
SH
Lai
Patrick F H
PF
Zhang
Qiu Wang
QW
Parker
Colleen H
CH
Suen
Renée S
RS
Hood
Roberta D
RD
Zhao
Yidan D
YD
Deng
Yupu
Y
Han
Robin N N
RN
Dumont
Daniel J
DJ
Stewart
Duncan J
DJ
D042683:Angiopoietin-1 / Q000235:genetics*; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000637:transplantation; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D011916:Rats, Inbred F344; D042787:Receptor, TIE-2 / Q000235:genetics; D012128:Respiratory Distress Syndrome / Q000473:pathology / Q000628:therapy*
D042683:Angiopoietin-1; D015815:Cell Adhesion Molecules; D016207:Cytokines; D008070:Lipopolysaccharides; D042787:Receptor, TIE-2