Abstract
Background
Sepsis in premature newborns is a risk factor for bronchopulmonary dysplasia (BPD), but underlying mechanisms of lung injury remain unclear. Aberrant expression of endothelial cell (EC) angiopoietin 2 (ANGPT2) disrupts angiopoietin 1 (ANGPT1)/TIE2-mediated endothelial quiescence, and is implicated in sepsis-induced acute respiratory distress syndrome in adults. We hypothesized that recombinant ANGPT1 will mitigate sepsis-induced ANGPT2 expression, inflammation, acute lung injury (ALI), and alveolar remodeling in the saccular lung.
Methods
Effects of recombinant ANGPT1 on lipopolysaccharide (LPS)-induced endothelial inflammation were evaluated in human pulmonary microvascular endothelial cells (HPMEC). ALI and long-term alveolar remodeling were assessed in newborn mice exposed to intraperitoneal LPS and recombinant ANGPT1 pretreatment.
Results
LPS dephosphorylated EC TIE2 in association with increased ANGPT2 in vivo and in vitro. ANGPT1 suppressed LPS and ANGPT2-induced EC inflammation in HPMEC. Neonatal mice treated with LPS had increased lung cytokine expression, neutrophilic influx, and cellular apoptosis. ANGPT1 pre-treatment suppressed LPS-induced lung Toll-like receptor signaling, inflammation, and ALI. LPS-induced acute increases in metalloproteinase 9 expression and elastic fiber breaks, as well as a long-term decrease in radial alveolar counts, were mitigated by ANGPT1.
Conclusions
In an experimental model of sepsis-induced BPD, ANGPT1 preserved endothelial quiescence, inhibited ALI, and suppressed alveolar simplification.
Impact
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Key message: Angiopoietin 1 inhibits LPS-induced neonatal lung injury and alveolar remodeling.
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Additions to existing literature:
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Demonstrates dysregulation of angiopoietin-TIE2 axis is important for sepsis- induced acute lung injury and alveolar simplification in experimental BPD.
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Establishes recombinant Angiopoietin 1 as an anti-inflammatory therapy in BPD.
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Impact: Angiopoietin 1-based interventions may represent novel therapies for mitigating sepsis-induced lung injury and BPD in premature infants.
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Acknowledgements
We thank Dr. Wei Yu and Dr. Chris Nitkin from Children’s Mercy Kansas City for their support with histologic and molecular techniques. We thank Dr. Nitkin, Dr. Yong Yun Han, and Dr. Geoffrey Allen from Children’s Mercy for their intellectual contributions. We wish to thank the Little Giraffe Foundation for grant support. Supported by 1R01HL128374-01 (VS) and Little Giraffe Foundation pilot grant (US).
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Conception and design: V.S., U.S. and H.M. Data collection: U.S., H.M., S.X. and S.M. Analysis and interpretation: V.S., U.S., H.M., S.M. and S.X. Drafting and editing the manuscript: U.S. wrote first draft of manuscript, V.S. and H.M. edited. V.S. approved final version for submission.
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Salimi, U., Menden, H.L., Mabry, S.M. et al. Angiopoietin-1 protects against endotoxin-induced neonatal lung injury and alveolar simplification in mice. Pediatr Res 91, 1405–1415 (2022). https://doi.org/10.1038/s41390-021-01544-0
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DOI: https://doi.org/10.1038/s41390-021-01544-0
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