Protective effect of endogenous PPARgamma against acute gastric mucosal lesions associated with ischemia-reperfusion.
Acute gastric mucosal lesions (AGMLs) are an important cause of gastrointestinal bleeding. Herein, we demonstrate that peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of a nuclear receptor family, functions as an endogenous anti-inflammatory pathway in a murine model of AGML induced by ischemia-reperfusion (I/R). Treatment with specific PPARgamma ligands such as BRL-49653, pioglitazone, or troglitazone was examined in a model of AGML induced by I/R. PPARgamma-deficient and wild-type mice were also examined for their response to I/R in stomach. Specific PPARgamma ligands exhibited dramatic and rapid protection against AGML formation associated with I/R in mice in a dose-dependent manner. In contrast, the AGML induced by I/R in PPARgamma-deficient mice was more severe than that observed in wild-type mice. Administration of the PPARgamma ligand significantly inhibited the upregulation of TNF-alpha, ICAM-1, inducible nitric oxide synthase, apoptosis, and nitrotyrosine formation induced by I/R in the stomach. These data indicate that an endogenous pathway associated with PPARgamma plays an important role in the pathogenesis of I/R-associated injury in the stomach.
Wada
Koichiro
K
Gastroenterology Division, Thorn 1419, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.
Nakajima
Atsushi
A
Takahashi
Hirokazu
H
Yoneda
Masato
M
Fujisawa
Nobutaka
N
Ohsawa
Emi
E
Kadowaki
Takashi
T
Kubota
Naoto
N
Terauchi
Yasuo
Y
Matsuhashi
Nobuyuki
N
Saubermann
Lawrence J
LJ
Nakajima
Noriko
N
Blumberg
Richard S
RS
D000818:Animals; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D013270:Stomach / Q000098:blood supply*; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse