Angiopoietin-1 increases survival and reduces the development of lung edema induced by endotoxin administration in a murine model of acute lung injury.
OBJECTIVE
To evaluate the effect of angiopoietin-1, an angiogenic growth factor, on lung capillary leakage and survival in a murine model of acute lung injury.


METHODS
Laboratory investigation.


METHODS
Research laboratory at New York University School of Medicine and Department of Veterans Affairs, NY Harbor Healthcare System.


METHODS
C57BL/6 mice weighing 18-20 g, susceptible to endotoxin-induced acute lung injury.


METHODS
Acute lung injury was induced in C57BL/6 mice by the intraperitoneal administration of endotoxin. The effects of angiopoietin-1, expressed from a nonreplicating E1a-deleted adenovirus containing the angiopoietin-1 complementary DNA (AdAng1), on survival and lung injury were evaluated. An E1a-deleted adenovirus that does not contain a transgene (Ad312) and phosphate-buffered saline were used as controls.


RESULTS
Angiopoietin-1 protein was detected by immunoblotting in the serum of mice that received an intraperitoneal injection of AdAng1 but not in mice that received the control virus Ad312. When compared with control groups, mice that received AdAng1 5 days before endotoxin administration had improved survival and significantly less protein leakage from the circulation into the lungs, as detected by quantitative spectrophotometric measurements of Evans blue dye. Furthermore, when compared with controls, histopathology and immunostaining of lungs against CD31 and smooth muscle actin suggested preservation of vascular integrity and decreased tissue damage in mice pretreated with AdAng1. When endotoxin administration preceded infection with AdAng1 by 3 hrs, no benefit was observed.


CONCLUSIONS
These data show that adenoviral mediated expression of angiopoietin-1 can protect against the development of lung capillary protein leak and decrease the mortality induced by endotoxin. However, the timing of AdAng1 administration in relation to the onset of lung injury may be critical.
Huang
Yao Qi
YQ
Division of Pulmonary & Critical Care Medicine, New York University School of Medicine, New York Campus, USA.
Sauthoff
Harald
H
Herscovici
Pablo
P
Pipiya
Teona
T
Cheng
Jin
J
Heitner
Sheila
S
Szentirmai
Oskar
O
Carter
Bob
B
Hay
John G
JG
D042683:Angiopoietin-1 / Q000097:blood / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004731:Endotoxins; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D011654:Pulmonary Edema / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D012016:Reference Values; D016896:Treatment Outcome
D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D004731:Endotoxins; D008070:Lipopolysaccharides; C433788:lipopolysaccharide, E. coli O26-B6