title: Cell-based angiopoietin-1 gene therapy for acute lung injury.
abstract: 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.
authors.affiliation: St. Michael's Hospital, Toronto, ON, M5B 1W8, Canada.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: McCarter
authors.forename: Shirley H J
authors.initials: SH
authors.lastname: Mei
authors.forename: Patrick F H
authors.initials: PF
authors.lastname: Lai
authors.forename: Qiu Wang
authors.initials: QW
authors.lastname: Zhang
authors.forename: Colleen H
authors.initials: CH
authors.lastname: Parker
authors.forename: Renée S
authors.initials: RS
authors.lastname: Suen
authors.forename: Roberta D
authors.initials: RD
authors.lastname: Hood
authors.forename: Yidan D
authors.initials: YD
authors.lastname: Zhao
authors.forename: Yupu
authors.initials: Y
authors.lastname: Deng
authors.forename: Robin N N
authors.initials: RN
authors.lastname: Han
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dumont
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
mesh_terms: 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*
chemical_list: D042683:Angiopoietin-1; D015815:Cell Adhesion Molecules; D016207:Cytokines; D008070:Lipopolysaccharides; D042787:Receptor, TIE-2