ORIGINAL ARTICLE

Hypoxia inducible factor 1 and 2 overexpression in inflammatory bowel disease

A Giatromanolaki¹, E Sivridis¹, E Maltezos², D Papazoglou², C Simopoulos³, K C Gatter⁵, A L Harris⁶, M I Koukourakis⁴

¹ Department of Pathology, Democritus University of Thrace, PO Box 12, Alexandroupolis 68100, Greece
² Department of Internal Medicine, Democritus University of Thrace
³ Department of Surgery, Democritus University of Thrace
⁴ Department of Radiotherapy/Oncology, Democritus University of Thrace
⁵ Department of Pathology, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, OX3 9DS, UK
⁶ Cancer Research UK, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 7LJ, UK

Correspondence to:
Correspondence to:
Dr A Giatromanolaki, Department of Pathology, PO Box 12, Alexandroupolis 68100, Greece;
targ{at}her.forthnet.gr

Aims: Hypoxia inducible factors 1 and 2 (HIF1 and HIF2) are hypoxia regulated transcriptional factors, which control the expression of a variety of genes responsible for angiogenesis, glycolysis, and the inhibition of apoptosis. Because angiogenesis and tissue regeneration are integral components of the inflammatory process, this study was designed to investigate the role of HIF molecules in inflammatory bowel disease.

Methods: Surgical specimens from patients with active ulcerative colitis (UC) and Crohn’s disease (CD) were assessed immunohistochemically for HIF1 and HIF2 reactivity, and the expression of these molecules was compared with the expression of the angiogenic factors thymidine phosphorylase (TP), vascular endothelial growth factor (VEGF), and VEGF–KDR activated vasculature. The vascular density of the lesions was also assessed using anti-CD31 immunostaining.

Results: HIF1 was expressed focally (epithelial cells, stromal fibroblasts, and myocytes) in both UC and CD, whereas HIF2 was expressed focally in UC and diffusely in CD. TP expression was uniformly positive in both diseases. VEGF expression was absent in CD, and weakly positive in UC. The VEGF–KDR reactivity of the submucosal vasculature was only slightly increased in UC and CD compared with normal tissue. The inflammatory cells stained with HIF2 and TP in all cases, but the reactivity was generalised in CD and focal in UC. In both diseases, vascular density was significantly higher than that seen in normal tissue.

Conclusions: The discordant expression of HIF2 and VEGF in CD suggests an inherent deficiency of the intestine to respond to various stresses by the induction of VEGF. This finding should be investigated further.

Keywords: hypoxia inducible factor; thymidine phosphorylase; vascular endothelial growth factor; IBD, inflammatory bowel disease; KDR; ulcerative colitis; Crohn’s disease

Abbreviations: APAAP, alkaline phosphatase/antialkaline phosphatase; CD, Crohn’s disease; HIF, hypoxia inducible factor; KDR, kinase insert domain containing receptor; TBS, Tris buffered saline; TP, thymidine phosphorylase; UC, ulcerative colitis; VEGF, vascular endothelial growth factor

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