PMID- 15489957
OWN - NLM
STAT- MEDLINE
DCOM- 20041201
LR  - 20240314
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 114
IP  - 8
DP  - 2004 Oct
TI  - Epithelial hypoxia-inducible factor-1 is protective in murine experimental 
      colitis.
PG  - 1098-106
AB  - Mucosal epithelial cells are uniquely equipped to maintain barrier function even 
      under adverse conditions. Previous studies have implicated hypoxia in mucosal 
      tissue damage resulting from both acute and chronic inflammation. Given the 
      importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) 
      for adaptive hypoxia responses, we hypothesized that HIF-1 may serve as a 
      barrier-protective element during mucosal inflammation. Initial studies of 
      hapten-based murine colitis revealed extensive mucosal hypoxia and concomitant 
      HIF-1 activation during colitis. To study this in more detail, we generated 2 
      mouse lines with intestinal epithelium-targeted expression of either mutant Hif1a 
      (inability to form HIF-1) or mutant von Hippel-Lindau gene (Vhlh; constitutively 
      active HIF-1). Studies of colitis in these mice revealed that decreased HIF-1 
      expression correlated with more severe clinical symptoms (mortality, weight loss, 
      colon length), while increased HIF levels were protective in these parameters. 
      Furthermore, colons with constitutive activation of HIF displayed increased 
      expression levels of HIF-1-regulated barrier-protective genes (multidrug 
      resistance gene-1, intestinal trefoil factor, CD73), resulting in attenuated loss 
      of barrier during colitis in vivo. Taken together, these studies provide insight 
      into tissue microenvironmental changes during model inflammatory bowel disease 
      and identify HIF-1 as a critical factor for barrier protection during mucosal 
      insult.
FAU - Karhausen, Jorn
AU  - Karhausen J
AD  - Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's 
      Hospital, Boston, Massachusetts 02115, USA.
FAU - Furuta, Glenn T
AU  - Furuta GT
FAU - Tomaszewski, John E
AU  - Tomaszewski JE
FAU - Johnson, Randall S
AU  - Johnson RS
FAU - Colgan, Sean P
AU  - Colgan SP
FAU - Haase, Volker H
AU  - Haase VH
LA  - eng
GR  - P01 DE13499/DE/NIDCR NIH HHS/United States
GR  - K08 DK002668-05/DK/NIDDK NIH HHS/United States
GR  - R01 HL060569/HL/NHLBI NIH HHS/United States
GR  - R01 DK050189/DK/NIDDK NIH HHS/United States
GR  - R03 DK062060/DK/NIDDK NIH HHS/United States
GR  - DK062060/DK/NIDDK NIH HHS/United States
GR  - DK02668/DK/NIDDK NIH HHS/United States
GR  - P01 DE013499/DE/NIDCR NIH HHS/United States
GR  - R29 DK050189/DK/NIDDK NIH HHS/United States
GR  - R37 DK050189/DK/NIDDK NIH HHS/United States
GR  - DK50189/DK/NIDDK NIH HHS/United States
GR  - HL60569/HL/NHLBI NIH HHS/United States
GR  - K08 DK002668/DK/NIDDK NIH HHS/United States
GR  - R03 DK062060-01/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/genetics/metabolism
MH  - Cell Hypoxia
MH  - Colitis/chemically induced/*metabolism/pathology/physiopathology
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Gene Deletion
MH  - Gene Expression Regulation
MH  - Genes, Reporter
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Intestinal Mucosa/cytology/*metabolism/*pathology
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Mice, Transgenic
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Recombination, Genetic
MH  - Transcription Factors/genetics/*metabolism
PMC - PMC522241
EDAT- 2004/10/19 09:00
MHDA- 2004/12/16 09:00
PMCR- 2004/10/15
CRDT- 2004/10/19 09:00
PHST- 2004/01/15 00:00 [received]
PHST- 2004/08/31 00:00 [accepted]
PHST- 2004/10/19 09:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/10/19 09:00 [entrez]
PHST- 2004/10/15 00:00 [pmc-release]
AID - JCI200421086 [pii]
AID - 21086 [pii]
AID - 10.1172/JCI21086 [doi]
PST - ppublish
SO  - J Clin Invest. 2004 Oct;114(8):1098-106. doi: 10.1172/JCI21086.