Endogenous PPAR gamma mediates anti-inflammatory activity in murine ischemia-reperfusion injury.
OBJECTIVE
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the regulation of intestinal inflammation. We sought to determine whether PPAR gamma could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury.


METHODS
PPAR gamma-deficient and wild-type mice were examined for their response to I/R procedure. Treatment with a PPAR gamma-specific ligand was also performed.


RESULTS
In a murine model of intestinal I/R injury, we observed more severe injury in PPAR gamma-deficient mice and protection against local and remote tissue injury in mice treated with a PPAR gamma-activating ligand, BRL-49653. Activation of PPAR gamma resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor alpha messenger RNA levels most likely by inhibition of the NF-kappa B pathway.


CONCLUSIONS
These data strongly suggest that an endogenous PPAR gamma pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries.
Nakajima
A
A
Gastroenterology Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Wada
K
K
Miki
H
H
Kubota
N
N
Nakajima
N
N
Terauchi
Y
Y
Ohnishi
S
S
Saubermann
L J
LJ
Kadowaki
T
T
Blumberg
R S
RS
Nagai
R
R
Matsuhashi
N
N
D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D005753:Gastric Mucosa / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000032:analysis; D011014:Pneumonia / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000276:immunology* / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D000077154:Rosiglitazone; D013270:Stomach / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D007004:Hypoglycemic Agents; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D018799:Intercellular Adhesion Molecule-1; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase