Relationship between inflammation and tissue hypoxia in a mouse model of chronic colitis.
BACKGROUND
Hypoxia has been reported to be associated with the colonic inflammation observed in a chemically induced mouse model of self-limiting colitis, suggesting that low tissue oxygen tension may play a role in the pathophysiology of inflammatory tissue injury. However, no studies have been reported evaluating whether tissue hypoxia is associated with chronic gut inflammation. Therefore, the objective of the present study was to determine whether hypoxia is produced within the colon during the development of chronic gut inflammation.


METHODS
Adoptive transfer of CD4(+) T cells obtained from interleukin-10-deficient (IL-10(-/-)) mice into lymphopenic recombinase-activating gene-1-deficient (RAG(-/-)) mice induces chronic colonic inflammation, with the inflammation ranging from mild to severe as determined by blinded histological analyses. Colonic blood flow, hematocrit, and vascular density were determined using standard protocols, whereas tissue hypoxia was determined using the oxygen-dependent probe pimonidazole.


RESULTS
Adoptive transfer of IL-10(-/-) CD4(+) T cells into RAG(-/-) recipients induced chronic colonic inflammation that ranged from mild to severe at 8 weeks following T-cell transfer. The colitis was characterized by bowel wall thickening, goblet cell dropout, and inflammatory infiltrate. Surprisingly, we found that animals exhibiting mild colonic inflammation had increased hypoxia and decreased systemic hematocrit, whereas mice with severe colitis exhibited levels of hypoxia and hematocrit similar to healthy controls. In addition, we observed that the extent of hypoxia correlated inversely with hematocrit and vascular density.


CONCLUSIONS
Changes in hematocrit, vascular density, and inflammatory state appear to influence the extent of tissue oxygenation in the T-cell-mediated model of chronic gut inflammation.
Harris
Norman R
NR
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA. nharr6@lsuhsc.edu
Carter
Patsy R
PR
Yadav
Amit Singh
AS
Watts
Megan N
MN
Zhang
Songlin
S
Kosloski-Davidson
Melissa
M
Grisham
Matthew B
MB
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation*; D002908:Chronic Disease; D003092:Colitis / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism*; D016753:Interleukin-10 / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice
D018398:Homeodomain Proteins; C064658:RAG-1 protein; D016753:Interleukin-10