Angiopoietin-1 attenuates lipopolysaccharide-induced endotoxemia in a Hirschsprung’s disease murine model by improving intestinal vascular integrity: implications for treating postoperative Hirschsprung-associated enterocolitis
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In brief
In brief
This preclinical study demonstrates that angiopoietin-1 (Ang1) reduces LPS-induced intestinal inflammation in a Hirschsprung disease mouse model by strengthening vascular barrier integrity and downregulating pro-inflammatory genes. The findings suggest Ang1 may offer a therapeutic approach for preventing or treating Hirschsprung-associated enterocolitis, a serious postoperative complication.
- Angiopoietin-1 pretreatment significantly reduced LPS-induced intestinal inflammation in Hirschsprung's disease mice.
- Ang1 downregulated pro-inflammatory markers (IL-1β, SELE, VEGFA, Ang2) in normoganglionic ileum after endotoxin challenge.
- Ang1 improved intestinal vascular barrier integrity by increasing phospho-TIE2 and VE-cadherin expression.
- Hirschsprung mice showed heightened inflammatory response to LPS compared to wild-type, suggesting baseline vascular vulnerability.
- Ang1 may offer therapeutic potential for preventing or treating Hirschsprung-associated enterocolitis by stabilizing endothelial barriers.
Written by the GCMD Library team from the article.
Abstract
Purpose
Angiopoietin-1 (Ang1) mitigates inflammation as a proangiogenic growth factor. Action of Ang1 on lipopolysaccharide (LPS)-induced endotoxemic inflammation was investigated in endothelin receptor-B null Hirschsprung’s disease mice (KO).
Methods
LPS or saline was injected intraperitoneally in KO (KO-LPS; n = 9, KO-sal; n = 5) and wild-type (WT) (WT-LPS; n = 6, WT-sal; n = 6) pups obtained within 24 h of birth. Normoganglionic terminal ileum harvested 6 h after LPS was used for RNA extraction and histology. IL-1β, SELE, VEGFA, Ang1, Angiopoietin-2 (Ang2), and TIE2 expression analyzed by quantitative polymerase chain reaction (qPCR), vascular permeability assessed by the Miles assay, severity of inflammation, and immunofluorescence for phospho-TIE2 and VE-cadherin were used to assess endothelial cell contact integrity and compared with KO pups pretreated with intraperitoneal Ang1 [Ang1(KO-LPS); n = 5] or saline [sal(KO-LPS); n = 6] 2 h before LPS.
Results
KO-LPS pups showed significantly increased inflammation (p < 0.05) and expression of IL-1β, SELE, VEGFA, and Ang2 (p = 0.019, 0.003, 0.008 and < 0.0001, respectively); expression of Ang1 and TIE2 remained unchanged when compared with KO-saline. In Ang1(KO-LPS) ileum, changes seen in sal(KO-LPS) were eliminated and phospho-TIE2 and VE-cadherin fluorescence increased.
Conclusion
Ang1 successfully attenuated LPS-induced normoganglionic intestinal inflammation, downregulated pro-inflammatory genes, and improved vascular barrier integrity in KO pups.