Tissue hypoxia in pathogenesis of ulcerative colitis: should we change all our beliefs?

Department of Surgery, University of Minnesota, Minneapolis, USAMany studies have focused on the role of irregularmucosal immune response, but there are noteworthyevidences regarding the role of ischemia in pathogen-esis of ulcerative colitis (UC). Hypoxia-induciblefactor-1 alpha (HIF1a) is an intranuclear proteinwhich is produced by decreased level of intracellularoxygen level. Increased levels of HIF1a in tissuespecimens and high levels of vascular endothelialgrowth factor (VEGF) in serum samples of UCpatients are novel findings, strongly congruent withthe role of ischemia in UC pathogenesis. The aim ofthis study is to evaluate the value of tissue hypoxia incellular level in pathogenesis of UC [1–3].Forty subjects in four groups were enrolled inour case control study as follows: 1) ten patientswithleftUC(toobtainbiopsyspecimensfromsparingpartsofthecolon);2)tenhealthyindividuals(referreddue to screening purposes); 3) ten formalin-fixedparaffin-embedded (FFPE) tissue samples frompatients with mesenteric ischemia; and 4) ten FFPEsamples from patients with infectious colitis. Subjectsin group 1 and 2 underwent colonoscopy. In group 1,two biopsy samples were taken, one from ulcerativetissue, and the other from spared intestinal tissue.In group 2, biopsy specimens were obtained from theleft colon. All subjects were evaluated for tissue hyp-oxia by a single expert pathologist utilizing HIF1aimmunohistochemical staining (Novus BiologicalsCompany, Clone ESEE122). Systemic and perirectalarteriolar oxygen saturation was then evaluated ingroups 1 and 2. Systemic oxygen saturation was mea-sured by radial artery blood sampling. Endoscopicultrasound was used for arteriolar blood sampling inperirectal level. The venules and arterioles were dis-tinguished according to wall thickness (Figure 1).Oxygen saturation was quantified within one minuteof blood sampling.Nine (90%) of the biopsy specimens of patientswith ulcerative colitis (ulcerative parts) as well as8 (80%) of the specimens of the subjects with mesen-teric ischemia showedtissue hypoxia in HIF-1a stain-ing. By contrast, only 1 (10%) of the biopsy samplesfrom subjects with infectious colitis and none of thesamples from healthy individuals and samples fromsparing parts of the colon of patients with UChad tissue hypoxia. There were no significant differ-ences between systemic saturation in groups 1 and2 (94.4 vs. 94.3%, p = 0.8), but pericapillary satura-tion was significantly higher in ulcerative colitispatients (96.4 vs. 94.3%, p = 0.001).Our data suggest that ischemia is the main pathol-ogy in a majority of UC patients. In support of ourconclusion, previous studies have shown that HIF1ais involved in triggering cell immune response [4] and