Article Text
Abstract
Background Elevated plasma levels of angiopoietin-2 (ANGPT2) have been reported in patients with acute lung injury (ALI); however, it remains unclear whether this increase contributes to, or just marks, the underlying vasculopathic inflammation and leak associated with ALI. Here we investigated the biological consequences of inducing high circulating levels of ANGPT2 in a mouse model of endotoxin-induced ALI.
Methods Transgenic mice (ANGPT2OVR) with elevated circulating levels of ANGPT2, achieved through conditional hepatocyte-specific overexpression, were examined from 3 to 72 hours following lipopolysaccharide (LPS)-induced ALI. An aptamer-based inhibitor was used to neutralise the effects of circulating ANGPT2 in LPS-exposed ANGPT2OVR mice.
Results Total cells, neutrophils and macrophages, as well as inflammatory cytokines, were significantly higher in bronchoalveolar lavage (BAL) of ANGPT2OVR versus littermate controltTA mice at 48 hours and 6 hours post-LPS, respectively. In contrast, LPS-induced vascular leak, evidenced by total BAL protein levels and lung wet/dry ratio, was unchanged between ANGPT2OVR and controlstTA, while BAL levels of IgM and albumin were decreased in ANGPT2OVR mice between 24 hours and 48 hours suggesting a partial attenuation of vascular leak. There was no significant difference in LPS-induced mortality between ANGPT2OVR and controlstTA. An ANGPT2-neutralising aptamer partially attenuated alveolar cell infiltration while exacerbating vascular leak in LPS-exposed ANGPT2OVR mice, supported by underlying time-dependent changes in the lung transcriptional profiles of multiple genes linked to neutrophil recruitment/adhesion and endothelial integrity.
Conclusions Our findings suggest that high circulating ANGPT2 potentiates endotoxin-induced lung inflammation but may also exert other pleiotropic effects to help fine-tune the vascular response to lung injury.
- Ards
- bacterial Infection
- cytokine biology
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Statistics from Altmetric.com
Footnotes
Contributors Conception and design: KS and SHJM; data acquisition: KS, MT, YD, SHJM and LM; analysis and interpretation: KS, MT, YD, SHJM and DJS; and manuscript preparation: KS, MT, SHJM and DJS.
Funding This work was supported by the Canadian Institutes of Health Research (MOP82791 to DJS), CREST Ontario Research Excellence Fund (GL2-01-042 to DJS) and Heart & Stroke Foundation of Canada (KS).
Competing interests None declared.
Ethics approval Ottawa Hospital Research Ethics Board.
Provenance and peer review Not commissioned; externally peer reviewed.