Rosiglitazone and 15‐deoxy‐Δ^12,14‐prostaglandin J₂, ligands of the peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), reduce ischaemia/reperfusion injury of the gut

Abstract

The peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) is a member of the nuclear receptor superfamily of ligand‐dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The thiazolidinedione rosiglitazone and the endogenous cyclopentenone prostaglandin (PG)D2 metabolite, 15‐deoxy‐Δ12,14‐PGJ2 (15d‐PGJ2), are two PPAR‐γ ligands, which modulate the transcription of target genes. The aim of this study was to investigate the effect of rosiglitazone and 15d‐PGJ2 on the tissue injury caused by ischaemia/reperfusion (I/R) of the gut. I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the coeliac trunk for 45 min, followed by release of the clamp allowing reperfusion for 2 or 4 h. This procedure results in splanchnic artery occlusion (SAO) shock. 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 for histological examination and biochemical studies. Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, significant increases in plasma tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β levels and marked injury to the distal ileum. 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. Administration at 30 min prior to the onset of gut ischaemia of the two PPAR‐γ agonists (rosiglitazone (0.3 mg kg−1 i.v.) and 15d‐PGJ2 (0.3 mg kg−1 i.v.)) significantly reduced the (i) fall in mean arterial blood pressure, (ii) mortality rate, (iii) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), (iv) lipid peroxidation (MDA levels), (v) production of proinflammatory cytokines (TNF‐α and IL‐1β) and (vi) histological evidence of gut injury. Administration of rosiglitazone and 15d‐PGJ2 also markedly reduced the nitrotyrosine formation and the upregulation of ICAM‐1 during reperfusion. In order to elucidate whether the protective effects of rosiglitazone and 15d‐PGJ2 are related to the activation of the PPAR‐γ receptor, we also investigated the effect of a PPAR‐γ antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone and 15d‐PGJ2. BADGE (1 mg kg−1 administered i.v. 30 min prior to the treatment of rosiglitazone or 15d‐PGJ2) significantly antagonised the effect of the two PPAR‐γ agonists and thus abolished the protective effect against gut I/R. These results demonstrate that the two PPAR‐γ agonists, rosiglitazone and 15d‐PGJ2, significantly reduce I/R injury of the intestine. British Journal of Pharmacology (2003) 140, 366–376. doi:

Rosiglitazone, an agonist of peroxisome proliferator-activated receptor γ, reduces pulmonary inflammatory response in a rat model of endotoxemia

“…Additionally, previous studies indicates that ligand-activated PPAR-g can downregulate NF-kB transcription [10,14]. In line with these fi ndings, in vivo treatment with rosiglitazone has been shown to attenuate the development of acute infl ammation [15], the development of zymosan-induced nonseptic shock [16], and the degree of ischemia-reperfusion injury in gut [17]. More recently, Birrell et al [18] have reported that PPAR-g agonists, rosiglitazone and SB 219994, inhibit aerosolized LPS-induced airway neutrophilia and associated release of pro-infl ammatory cytokines (granulocytecolony stimulating factor and keratinocyte-derived chemokine) in the mouse lung.…”

Involvement of PPAR nuclear receptors in tissue injury and wound repair

“…These protective effects are attenuated by PPARγ antagonists or reduction of PPARγ levels in mutant PPARγ heterozygous animals (32,34). Similarly, activation of PPARα attenuates I/R injury by reducing ICAM-1 expression, peroxynitrite activity, and the production of proinflammatory cytokines (35).…”

Nitro-Oleic Acid Attenuates OGD/R-Triggered Apoptosis in Renal Tubular Cells via Inhibition of Bax Mitochondrial Translocation in a PPAR-γ-Dependent Manner

“…Ligands for PPAR-γ include natural compounds such as eicosanoids, oxidized phospholipids, 15-deoxy-Δ12,14-PGJ2 and drugs such as the thiazolidinedione derivative rosiglitazone [8], and have been reported to ameliorate ischemia and reperfusion injury in a PPAR-γ dependent manner. The PPAR-γ antagonist, bisphenol A diglycidyl ether (BADGE) abolishes the protection afforded by rosiglitazone and 15d-PGJ2 in a rat model of intestinal I/R [49]. Moreover, rosiglitazone (10 mg/kg) inhibits stomach I/R injury in the heterozygous PPAR-γ-deficient mice, even via activation of reduced levels of PPAR-γ [50].…”