Protective effects of preischemic treatment with pioglitazone, a peroxisome proliferator-activated receptor-gamma ligand, on lung ischemia-reperfusion injury in rats.
OBJECTIVE
Lung injury induced by ischemia-reperfusion is the main cause of early graft failure after lung transplantation, which may result from oxygen-free radicals, inflammatory cytokine production, and polymorphonuclear leukocyte accumulation into the interstitium, resulting in severe lung edema. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) belongs to the nuclear receptor superfamily and has an anti-inflammatory effect by preventing the activation of transcription factors such as nuclear factor-kappaB (NF-kappaB). NF-kappaB regulates the expression of many genes of early response products in the development of acute inflammation. We examined the effects of pioglitazone, a synthetic ligand of PPAR-gamma, against lung ischemia-reperfusion injury in rats.


METHODS
The left lungs of male Wistar rats were rendered ischemic for 90 min and then reperfused for 2 h. Treated animals received pioglitazone (10 mg/kg) 2 h before induction of ischemia. Lung injury was quantified in terms of lung microvascular permeability (Evans blue dye extravasation), tissue lipid peroxidation (thiobarbituric acid reactive substances), and tissue polymorphonuclear leukocyte accumulation (myeloperoxidase activity). The tissue concentrations of tumor necrosis factor-alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant-1 (CINC-1) were also measured. Statistical analyses were performed by one-way analysis of variance, followed by Sheffe's multiple comparison test.


RESULTS
The lung vascular permeability in pioglitazone-treated animals was reduced by 55% of the increase of Evans blue dye extravasation relative to control animals (P=0.003). The protective effects of pioglitazone treatment were correlated with the reduction by 79% of the increase of thiobarbituric acid reactive substances (P=0.045) and the reduction by 58% of myeloperoxidase activity increase (P<0.001). The production of TNF-alpha was reduced by 63% of the increase (P<0.001) and the reduction of CINC-1 was 45% (P<0.001). Pioglitazone did not affect the lung in the sham animals.


CONCLUSIONS
Pioglitazone treatment before ischemia attenuated lung ischemia-reperfusion injury in rats. The mechanism of these protective effects involves inhibition of the production of proinflammatory cytokines, polymorphonuclear leukocyte accumulation, and tissue lipid peroxidation, resulting in reduced lung edema.
Ito
Kazuhiro
K
Department of Cardiovascular and Thoracic Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. kazuitoh@koto.kpu-m.ac.jp
Shimada
Junichi
J
Kato
Daishiro
D
Toda
Shogo
S
Takagi
Tomohisa
T
Naito
Yuji
Y
Yoshikawa
Toshikazu
T
Kitamura
Nobuo
N
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D008024:Ligands; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000098:blood supply; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D000077205:Pioglitazone; D020011:Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014157:Transcription Factors / Q000378:metabolism*
D016207:Cytokines; D008024:Ligands; D020011:Protective Agents; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D009195:Peroxidase; D000077205:Pioglitazone