Cell-based Angiopoietin-1 Gene Therapy for Acute Lung Injury

McCarter, Sarah D.; Mei, Shirley H. J.; Lai, Patrick F.H.; Zhang, Qiu Wang; Parker, Colleen H.; Suen, Renée S.; Hood, Roberta D.; Zhao, Yidan; Deng, Yupu; Han, Rui; Dumont, Daniel; Stewart, Duncan J.

doi:10.1164/rccm.200609-1370oc

Cited by 138 publications

(102 citation statements)

References 50 publications

(57 reference statements)

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“…Although Ang-1 was preventing development of these important aspects of VILI, it did not influence the end points of VILI such as vascular leakage and impaired gas exchange (Hegeman et al, 2010). Our data are in apparent contrast with previously reported protective effects of Ang-1 on vascular leakage in endotoxin-challenged animals (Huang et al, 2008;McCarter et al, 2007;Mei et al, 2007;Witzenbichler et al, 2005). Using a similar dosing and administration procedure of Ang-1, David et al showed that Ang-1 therapy also stabilized endothelial barrier function in an murine model of polymicrobiological abdominal sepsis as evidenced by attenuation of protein leakage from lung capillaries into the alveolar compartment (David et al, 2011).…”

Section: Inhibition Of Ventilator-induced Lung Inflammation: Does It contrasting

confidence: 97%

Ventilator-Induced Lung Injury: Mechanisms and Future Therapeutic Interventions

Hegeman¹,

Schultz²,

Heijnen³

et al. 2012

Front Lines of Thoracic Surgery

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Section: Inhibition Of Ventilator-induced Lung Inflammation: Does It contrasting

confidence: 97%

Ventilator-Induced Lung Injury: Mechanisms and Future Therapeutic Interventions

Hegeman¹,

Schultz²,

Heijnen³

et al. 2012

Front Lines of Thoracic Surgery

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“…Recombinant ANG1, inhibition of ANG2 or increasing Tie2 activity by therapeutic antibodies or a small-molecule phosphatase inhibitor have vascular protective effects in acute inflammation and in sepsis (32,33,34,62,72,73), consistent with an agonist action of ANG1 and antagonistic action of ANG2. Reduced Tie2 protein and Tie2 and Ang1 mRNA levels have been reported in murine sepsis and systemic inflammation (56,74).…”

Section: Methodsmentioning

confidence: 82%

“…Reduced Ang2 gene dosage (31), ANG2 blocking antibodies (32), and ectopic ANG1 reduce sepsis-induced vascular leak and lung injury in mice (33). In comparison, mice expressing reduced Tie2 levels are more susceptible to LPS-induced endotoxemia (34,35). ANG2 inhibition also reduces the harmful inflammation associated with cardiac transplant rejection (36) and improves endothelial-pericyte interactions in diabetic retinopathy (37).…”

Section: Resultsmentioning

confidence: 99%

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Korhonen

Lampinen

Giri³

et al. 2016

Journal of Clinical Investigation

195

279

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The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β 1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1-and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability. The Journal of Clinical Investigation R E S E A R C H A R T I C L E3 4 9 6 jci.org Volume 126 Number 9 September 2016We found that angiopoietins promoted a direct interaction of Tie1 and Tie2 and that this interaction was regulated by integrin β 1 . ANG1-and ANG2-induced Tie2 activation and vascular remodeling were reduced or absent in mice where Tie1 was deleted in vascular endothelial cells. Tie1 deletion also attenuated ANG1-induced Akt activation and nuclear exclusion of FOXO1. We found that Tie1 was suppressed via ectodomain cleavage during acute inflammation and that this was associated with reduced agonistic activity of ANG2 and decreased Tie2 signaling. These results indicate that the agonist action of ANG2 is attenuated in inflammation and that Tie1 is an essential component of the angiopoietin signaling system that has potential for therapeutic targeting in disease. ResultsAngiopoietins induce direct interaction of Tie1 and Tie2. To investigate the dynamics of the Tie receptors in angiopoietin signaling, we transfected HUVECs with retroviral vectors expressing full-length (FL) Tie1 and Tie2, tagged on the C terminus with mCherry and GFP, respectively. Stimulation of FL-Tie2-GFP and FL-Tie1-mCherry expressing endothelial cells with COMP-Ang1 (CAng1) (49) or with recombinant human ANG2 induced colocalization of Tie1 and Tie2 in endothelial cell-cell junctions ( Figure 1A and Supplemental Video 1; supplemental material available online with this article; doi:10.1172/JCI84923DS1) (44,45,50). To investigat...

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“…Other small clinical studies demonstrated that circulating Ang-2 levels correlated with the APACHE and SOFA scoring systems as well as with the 28-day mortality reflecting disease severity and prognosis (Fiedler et al 2006;Kranidioti et al 2009;McCarter et al 2007;Orfanos et al 2007;Thurston et al 2000;Thurston et al 1999;Witzenbichler et al 2005).…”

Section: Ang-1 and -2mentioning

confidence: 92%