WY 14643, a potent exogenous PPAR-α ligand, reduces intestinal injury associated with splanchnic artery occlusion shock

Salvatore Cuzzocrea, Rosanna Di Paola, Emanuela Mazzon, Tiziana Genovese, Carmelo Muià, Achille P. Caputi

Research output: Contribution to journalArticlepeer-review

Abstract

The peroxisome proliferator-activated receptor-α (PPAR-α) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. WY 14643 is a potent PPAR-α ligand that modulates the transcription of target genes. The aim of this study was to investigate the effect of WY 14643 on the tissue injury caused by ischemia-reperfusion (I/R) of the gut. I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamp, allowing reperfusion for 2 h 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 20% of the animals survived for the entire 4-h reperfusion period. Surviving animals were sacrificed for histological examination and biochemical studies. Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity, significant increases in plasma tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels, and marked injury to the distal ileum. Increased immunoreactivity to nitrotyrosine and polyadenosine diphosphate [ADP]-ribose (PAR) 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 or with anti-P-selectin antibody resulted in diffuse staining. Administration of WY 14643 (1 mg/kg i.v.) 30 min before the onset of gut ischemia significantly reduced the (a) fall in mean arterial blood pressure, (b) mortality rate, (c) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), (d) production of proinflammatory cytokines (TNF-α and IL-1β), and (e) histological evidence of gut injury. Administration of WY 14643 also markedly reduced the nitrotyrosine formation, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) activation, up-regulation of ICAM-1, and expression of P-selectin during reperfusion. These results demonstrate that the PPAR-α agonist WY 14643 significantly reduces I/R injury of the intestine.

Original languageEnglish
Pages (from-to)340-346
Number of pages7
JournalShock
Volume22
Issue number4
DOIs
Publication statusPublished - Oct 2004

Keywords

  • Ischemia-reperfusion shock
  • PARP-α
  • Splanchnic artery occlusion
  • WY 14643

ASJC Scopus subject areas

  • Physiology
  • Critical Care and Intensive Care Medicine

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