期刊
GASTROENTEROLOGY
卷 134, 期 1, 页码 145-155出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2007.09.033
关键词
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资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL060569] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [P01DE013499, P50DE016191] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK050189, T32DK007038, R37DK050189, R29DK050189] Funding Source: NIH RePORTER
- NHLBI NIH HHS [R01 HL060569-01A1, HL60569, R01 HL060569] Funding Source: Medline
- NIDCR NIH HHS [P01 DE013499, DE016191, P50 DE016191, P01 DE013499-010003, P50 DE016191-010002] Funding Source: Medline
- NIDDK NIH HHS [R01 DK050189-06, R01 DK050189, T32 DK007038, R29 DK050189, DK50189, R37 DK050189] Funding Source: Medline
Background & Aims: A number of recent studies have implicated tissue hypoxia in both acute and chronic inflammatory diseases, particularly as they relate to mucosal surfaces lined by epithelial cells. In this context, a protective role for the transcriptional regulator hypoxia-inducible factor (HIF) was shown through conditional deletion of epithelial HIF-1 alpha in a murine model of colitis. Here, we hypothesized that pharmacologic activation of HIF would similarly provide a protective adaptation to murine colitic disease. Methods: For these purposes, we used a novel prolyl hydroxylase (PHD) inhibitor (FG-4497) that readily stabilizes HIF-1 alpha and subsequently drives the expression downstream of HIF target genes (eg, erythropoietin). Results: Our results show that the FG-4497-mediated induction of HIF-1 alpha provides an overall beneficial influence on clinical symptoms [weight loss, colon length, tissue tumor necrosis factor-a (TNF alpha)] in murine trinitrobenzene sulfonic acid (TNBS) colitis, most likely because of their barrier protective function and wound healing during severe tissue hypoxia at the site of inflammation. Conclusions: Taken together these findings emphasize the role of epithelial HIF-1 alpha during inflammatory diseases in the colon and may provide the basis for a therapeutic use of PHD inhibitors in inflammatory mucosal disease.
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