title: Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function.
abstract: OBJECTIVE
  Hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors are protective in mouse models of inflammatory bowel disease (IBD). Here, we investigated the therapeutic target(s) and mechanism(s) involved.
  
  
  METHODS
  The effect of genetic deletion of individual HIF-prolyl hydroxylase (PHD) enzymes on the development of dextran sulphate sodium (DSS)-induced colitis was examined in mice.
  
  
  RESULTS
  PHD1(-/-), but not PHD2(+/-) or PHD3(-/-), mice were less susceptible to the development of colitis than wild-type controls as determined by weight loss, disease activity, colon histology, neutrophil infiltration, and cytokine expression. Reduced susceptibility of PHD1(-/-) mice to colitis was associated with increased density of colonic epithelial cells relative to wild-type controls, which was because of decreased levels of apoptosis that resulted in enhanced epithelial barrier function. Furthermore, with the use of cultured epithelial cells it was confirmed that hydroxylase inhibition reversed DSS-induced apoptosis and barrier dysfunction. Finally, PHD1 levels were increased with disease severity in intestinal tissue from patients with IBD and in colonic tissues from DSS-treated mice.
  
  
  CONCLUSIONS
  These results imply a role for PHD1 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon. Genetic loss of PHD1 is protective against colitis through decreased epithelial cell apoptosis and consequent enhancement of intestinal epithelial barrier function. Thus, targeted PHD1 inhibition may represent a new therapeutic approach in IBD.
authors.affiliation: The Conway Institute, University College Dublin, Ireland.
authors.forename: Murtaza M
authors.initials: MM
authors.lastname: Tambuwala
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.forename: Colin R
authors.initials: CR
authors.lastname: Lenihan
authors.forename: Judit
authors.initials: J
authors.lastname: Kiss
authors.forename: Markus
authors.initials: M
authors.lastname: Stauch
authors.forename: Carsten C
authors.initials: CC
authors.lastname: Scholz
authors.forename: Peter
authors.initials: P
authors.lastname: Fraisl
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.forename: Martin
authors.initials: M
authors.lastname: Mollenhauer
authors.forename: Sean P
authors.initials: SP
authors.lastname: Saunders
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D009687:Nuclear Proteins; D016264:Dextran Sulfate; D049308:Dioxygenases; C522721:PHD1 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases