markers of hypoxia correlate with histologic and endoscopic severity of colitis in inflammatory bowel disease

Edwin F deZoeten,1,* Kayla D Battista,2,* Steven B Colson,1,* Mark A Lovell,3 Brittelle E Kessler,2 Robert W Isfort,2 Blair P Fennimore,2 Joseph C Onyiah,2 Daniel J Kao,2 Alyson Yeckes,1 Simon Keely,1,4 Monica Murray,2 Edward J Hoffenberg,1 Sean P Colgan,2 Mark E Gerich2 1Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA; 2Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA; 3Department of Pathology, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA; 4School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia *These authors contributed equally to this workCorrespondence: Edwin F deZoetenMucosal Inflammation Program, 12700 E. 19th Ave, Aurora, CO 80045, USATel +1 303-724-7239Fax +1 303-724-7243Email Edwin.dezoeten@childrenscolorado.orgBackground: Inflammation results in significant shifts in tissue metabolism. Recent studies indicate that inflammation and hypoxia occur concomitantly. We examined whether circulating and tissue markers of hypoxia could serve as surrogate indicators of disease severity in adult and pediatric patients with inflammatory bowel disease (IBD).Methods: Serum and colonic biopsies were obtained from pediatric subjects with active IBD colitis and adult subjects with active and inactive ulcerative colitis, along with healthy non-colitis controls of all ages. Disease activity was evaluated by endoscopy and histopathology. Levels of serum hypoxia markers (macrophage inflammatory protein-3α [MIP-3α], vascular endothelial growth factor [VEGF], and erythropoietin [EPO]) were measured.Results: Children with active IBD colitis had higher levels of serum MIP-3α and VEGF compared to non-colitis controls (p< 0.01 and p< 0.05, respectively). In adult subjects with endoscopically active ulcerative colitis, serum MIP-3α and EPO were significantly elevated compared to non-colitis controls (both p< 0.01). In parallel, analysis of colon tissue MIP-3α mRNA and protein in pediatric subjects revealed increased expression in those with IBD colitis compared to controls (p< 0.05 and p< 0.01 for mRNA and protein, respectively). Serum MIP-3α and VEGF significantly increased with histology grade.Conclusion: Peripheral blood hypoxia markers may be useful indicators of disease activity for pediatric and adult IBD patients.Keywords: Crohn’s disease, ulcerative colitis, mucosal inflammation, tissue histology