1 The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptorsuperfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormonereceptors. The thiazolidinedione rosiglitazone and the endogenous cyclopentenone prostaglandin(PG)D2 metabolite, 15-deoxy-D12,14-PGJ2 (15d-PGJ2), are two PPAR-gamma ligands, which modulate thetranscription of target genes.2 The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the tissueinjury caused by ischaemia/reperfusion (I/R) of the gut.3 I/R injury of the intestine was caused by clamping both the superior mesenteric artery and thecoeliac trunk for 45 min, followed by release of the clamp allowing reperfusion for 2or 4 h. Thisprocedure results in splanchnic artery occlusion (SAO) shock.4 Rats subjected to SAO developed a significant fall in mean arterial blood pressure, and only 10%of the animals survived for the entire 4 h reperfusion period. Surviving animals were killed forhistological examination and biochemical studies. Rats subjected to SAO displayed a significantincrease in tissue myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, significantincreases in plasma tumour necrosis factor (TNF)-a and interleukin (IL)-1b levels and marked injuryto the distal ileum.5 Increased immunoreactivity to nitrotyrosine was observed in the ileum of rats subjected to SAO.Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule(ICAM-1) antibody resulted in diffuse staining.6 Administration at 30 min prior to the onset of gut ischaemia of the two PPAR-g agonists(rosiglitazone (0.3 mg kg1 i.v.) and 15d-PGJ2 (0.3 mg kg1 i.v.)) significantly reduced the (i) fall inmean arterial blood pressure, (ii) mortality rate, (iii) infiltration of the reperfused intestine withpolymorphonuclear neutrophils (MPO activity), (iv) lipid peroxidation (MDA levels), (v) productionof proinflammatory cytokines (TNF-a and IL-1b) and (vi) histological evidence of gut injury.Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine formation andthe upregulation of ICAM-1 during reperfusion.7 In order to elucidate whether the protective effects of rosiglitazone and 15d-PGJ2are related to theactivation of the PPAR-g receptor, we also investigated the effect of a PPAR-g antagonist, bisphenol Adiglycidyl ether (BADGE), on the protective effects of rosiglitazone and 15d-PGJ2. BADGE (1mgkg1administered i.v. 30 min prior to the treatment of rosiglitazone or 15d-PGJ2) significantly antagonisedthe effect of the two PPAR-g agonists and thus abolished the protective effect against gut I/R.8 These results demonstrate that the two PPAR-g agonists, rosiglitazone and 15d-PGJ2, significantlyreduce I/R injury of the intestine.
Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, ligands of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), reduce ischaemia/reperfusion injury of the gut
Dugo L;
2003-01-01
Abstract
1 The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptorsuperfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormonereceptors. The thiazolidinedione rosiglitazone and the endogenous cyclopentenone prostaglandin(PG)D2 metabolite, 15-deoxy-D12,14-PGJ2 (15d-PGJ2), are two PPAR-gamma ligands, which modulate thetranscription of target genes.2 The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the tissueinjury caused by ischaemia/reperfusion (I/R) of the gut.3 I/R injury of the intestine was caused by clamping both the superior mesenteric artery and thecoeliac trunk for 45 min, followed by release of the clamp allowing reperfusion for 2or 4 h. Thisprocedure results in splanchnic artery occlusion (SAO) shock.4 Rats subjected to SAO developed a significant fall in mean arterial blood pressure, and only 10%of the animals survived for the entire 4 h reperfusion period. Surviving animals were killed forhistological examination and biochemical studies. Rats subjected to SAO displayed a significantincrease in tissue myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, significantincreases in plasma tumour necrosis factor (TNF)-a and interleukin (IL)-1b levels and marked injuryto the distal ileum.5 Increased immunoreactivity to nitrotyrosine was observed in the ileum of rats subjected to SAO.Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule(ICAM-1) antibody resulted in diffuse staining.6 Administration at 30 min prior to the onset of gut ischaemia of the two PPAR-g agonists(rosiglitazone (0.3 mg kg1 i.v.) and 15d-PGJ2 (0.3 mg kg1 i.v.)) significantly reduced the (i) fall inmean arterial blood pressure, (ii) mortality rate, (iii) infiltration of the reperfused intestine withpolymorphonuclear neutrophils (MPO activity), (iv) lipid peroxidation (MDA levels), (v) productionof proinflammatory cytokines (TNF-a and IL-1b) and (vi) histological evidence of gut injury.Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine formation andthe upregulation of ICAM-1 during reperfusion.7 In order to elucidate whether the protective effects of rosiglitazone and 15d-PGJ2are related to theactivation of the PPAR-g receptor, we also investigated the effect of a PPAR-g antagonist, bisphenol Adiglycidyl ether (BADGE), on the protective effects of rosiglitazone and 15d-PGJ2. BADGE (1mgkg1administered i.v. 30 min prior to the treatment of rosiglitazone or 15d-PGJ2) significantly antagonisedthe effect of the two PPAR-g agonists and thus abolished the protective effect against gut I/R.8 These results demonstrate that the two PPAR-g agonists, rosiglitazone and 15d-PGJ2, significantlyreduce I/R injury of the intestine.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
