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Stabilisation of epithelial hypoxia‐inducible factor reverses colitis through accelerated restitution (1111.3)
Author(s) -
Goggins Bridie,
Minahan Kyra,
Kostakis Anna,
Shalwitz Robert,
Horvat Jay,
Keely Simon
Publication year - 2014
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.28.1_supplement.1111.3
Subject(s) - colitis , wound healing , hypoxia (environmental) , inflammatory bowel disease , inflammation , integrin , pathology , epithelium , immunology , chemistry , cancer research , medicine , receptor , disease , organic chemistry , oxygen
During mucosal inflammation, changes in metabolic activity and vascular tissue damage, lead to a reduction in tissue‐oxygen tension (hypoxia), in which healing processes such as re‐epithelialisation occur. Previous work has shown that pharmacological induction of hypoxia‐inducible factor (HIF), a global transcriptional regulator of the hypoxic response, by prolyl hydroxylase inhibitors (PHDi) is protective in murine models of colitis. We have previously identified induction of integrin β1 (ITGB1) during hypoxia. As integrins play critical roles in epithelial wound healing, we hypothesised that pharmacological HIF activation accelerates epithelial restitution through integrin‐dependent pathways. We aimed to investigate the relative induction of integrin β1 heterodimers in epithelial cells by PHDi in vivo and in vitro . Colitis was induced in BalbC mice by rectal instillation of 2.5% TNBS. PHDi (Akebia‐4924, [5mg/Kg]) was administered by oral gavage. Colitis was monitored endoscopically over 7 Days with the Karl Storz coloview endoscope. Biopsies were taken on alternate days with a 20‐french biopsy forceps. Mice were euthanised and tissues and colonic epithelial cells were harvested for mRNA and protein. Scratch assays were performed on Caco‐2 monolayers seeded on 6 well plates. TNBS colitis led to a significant increase in ITGB1 transcript in epithelium, correlating (R2=0.71) disease severity. Mice treated with PHDi demonstrated advanced endoscopic healing compared to vehicle treated animals, concurrent with an earlier induction of ITGB1 and induction of epithelial integrins α3 and α6. Caco‐2 monolayers show accelerated wound healing in scratch assays when treated with 10mM PHDi which was inhibited by antibodies functionally targeting α3β1 and α6β1 integrin homodimers. These data suggest that mucosal HIF activation promotes healing through accelerated induction of epithelial intregrins. Grant Funding Source : National Health and Medical Research Council