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Inhibition of FLT‐1 Decreases the Incidence of Severe Necrotizing Enterocolitis in Neonatal Mice
Author(s) -
FrankKamenetskii Anastasia,
Yan Xiaocai,
Managlia Elizabeth,
De Plaen Isabelle
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04862
Subject(s) - necrotizing enterocolitis , medicine , enterocolitis , pathogenesis , antibody , hypoxia (environmental) , immunology , gastroenterology , pathology , chemistry , organic chemistry , oxygen
Necrotizing enterocolitis (NEC) is a common gastrointestinal disease among premature infants. While advances in clinical management have been achieved through therapeutical modalities and surgical interventions, serious limitation in the improvement of outcomes after the diagnosis remain, largely due to the complexity of underlying biology. Our previous study suggests that maldevelopment of the intestinal microvasculature plays an important role in NEC pathogenesis and that embryonic macrophages support intestinal microvasculature development by promoting VEGF/VEGFR2 signaling and endothelial cell proliferation. We also found that monocytes express VEGFR1 which is known to trap VEGF, making it unavailable to reach VEGFR2, and that during experimental NEC, intestinal monocyte recruitment and activation mediate intestinal tissue injury and blocking monocyte NF‐KB activation preserved intestinal microvascular density. However, the mechanism remains unclear. Here we hypothesize that blocking VEGFR1 protects against NEC. To test our hypothesis, littermates were injected with anti‐FLT‐1 antibodies (5mg/kg) or control IgG antibody (controls) and submitted one hour later to an established murine neonatal NEC model, which include inoculation with adult commensal bacteria, hypoxia, cold stress and formula feedings. Animals were euthanized when presenting signs of distress or after 72h. Intestinal tissues were collected for H&E staining and intestinal injury score determination. In pups treated with anti‐FLT‐1 antibodies, survival was significantly improved compared to control pups (median survival of 54h vs. 36 h respectively; p≤0.05). Moreover, intestinal injury score was significantly less in pups treated with anti‐FLT‐1 antibodies compared to littermate controls (10/29 vs 18/30 with NEC score ≥2, χ2=3.85, p≤0.05). In conclusion, our data shows that blocking FLT‐1 increases survival and protects against intestinal injury in a neonatal mouse NEC model, suggesting a role for FLT‐1 in NEC. Further investigation of this pathway may lead to the identification of potential therapeutic targets.