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Mucosal protection by hypoxia‐inducible factor (HIF) prolyl hydroxylase inhibition
Author(s) -
Keeley Simon,
Furuta Glenn T,
Colgan Sean P
Publication year - 2008
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.22.1_supplement.328.3
Subject(s) - hypoxia (environmental) , colitis , hypoxia inducible factors , inflammation , inflammatory bowel disease , regulator , wound healing , medicine , transcription factor , cancer research , proinflammatory cytokine , immunology , biology , disease , pathology , chemistry , gene , biochemistry , organic chemistry , oxygen
A number of recent studies have implicated tissue hypoxia in both acute and chronic inflammatory diseases, particularly as they relate to mucosal surfaces involving epithelial cells. In this context, a protective role for the transcriptional regulator hypoxia‐inducible factor (HIF) has been demonstrated through conditional deletion of epithelial HIF‐1α in a murine model of colitis. Here, we hypothesized that pharmacologic activation of HIF would similarly provide a protective adaptation to murine colitic disease. For these purposes, we used a novel prolyl hydroxylase (PHD) inhibitor (FG‐4497) which readily stabilizes HIF‐1α and subsequently drives the expression downstream HIF target genes (e.g. EPO). Our results show that the FG‐4497‐mediated induction of HIF‐1α provides an overall beneficial influence on clinical symptoms (weight loss, colon length, tissue IFN and TNF) in murine TNBS colitis, most likely due to their barrier protective function and wound healing during severe tissue hypoxia at the site of inflammation. Taken together these findings emphasize the role of epithelial HIF‐1α during inflammatory diseases in the colon and may provide the basis for a therapeutic use of PHD inhibitors in inflammatory mucosal disease.