Suppression of intestinal ischemia-reperfusion injury by a specific peroxisome proliferator-activated receptor-gamma ligand, pioglitazone, in rats.
Neutrophil activation and tumor necrosis factor-alpha (TNF-alpha) induction play a critical role in ischemia-reperfusion-induced intestinal inflammation. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, has recently been implicated as a regulator of inflammatory responses. The aim of the present study was to determine whether pioglitazone, a specific PPAR-gamma ligand, can ameliorate reperfusion-induced intestinal injury in rats, and whether the agent can inhibit the increase in neutrophil accumulation associated with TNF-alpha expression. Intestinal damage was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 30 min followed by reperfusion. Reperfusion after 30 min ischemia resulted in an increase in luminal protein concentrations with levels reaching a maximum after 60 min of reperfusion. In contrast, pretreatment with pioglitazone 2 h before ischemia inhibited the increase in luminal protein concentrations after 60 min reperfusion in a dose-dependent manner (1-30 mg/kg). The increase in tissue-associated myeloperoxidase activity, an index of neutrophil infiltration, after reperfusion was significantly inhibited by pretreatment with pioglitazone. Pioglitazone also inhibited increases in intestinal TNF-alpha protein and mRNA expression determined by ELISA and RT-PCR, respectively. In conclusion, activation of PPAR-gamma may represent a novel approach to the treatment of intestinal inflammation induced by ischemia-reperfusion.
Naito
Yuji
Y
First Department of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan. ynaito@koto.kpu-m.ac.jp
Takagi
Tomohisa
T
Uchiyama
Kazuhiko
K
Handa
Osamu
O
Tomatsuri
Naoya
N
Imamoto
Eiko
E
Kokura
Satoshi
S
Ichikawa
Hiroshi
H
Yoshida
Norimasa
N
Yoshikawa
Toshikazu
T
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000473:pathology; D008024:Ligands; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007004:Hypoglycemic Agents; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D000077205:Pioglitazone