Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia
Détails
ID Serval
serval:BIB_22B904A979EA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia
Périodique
Shock
ISSN
1073-2322 (Print)
Statut éditorial
Publié
Date de publication
08/2000
Volume
14
Numéro
2
Pages
134-41
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Aug
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Aug
Résumé
Peroxynitrite-mediated DNA strand breaks trigger poly (ADP-ribose) synthetase (PARS) activation, resulting in intracellular energetic failure and organ dysfunction. We investigated the role of PARS activation on the inflammatory and functional response of the intestine to mesenteric ischemia-reperfusion injury. Anesthetized rats exposed to 15 min occlusion of the superior mesenteric artery showed an increased mucosal PARS activity (ex vivo incorporation of radiolabelled NAD+ in gut mucosal scrapings) as soon as 10 min after reperfusion. During the first 30 min of reperfusion, significant mucosal damage developed, as well as mucosal hyperpermeability to a 4000 MW fluorescent dextran (FD4). These alterations were significantly reduced by treatment with the NO synthase inhibitor L-NMA, which blocks the production of peroxynitrite, as well as with the PARS inhibitors 3-aminobenzamide and nicotinamide, whereas they were markedly enhanced by the glutathione depletor L-buthionine-(S,R)-sulfoximine. Also, PARS inhibition significantly reduced ileal neutrophil infiltration (myeloperoxidase activity) at 3 h reperfusion. In a second set of experiments, the effects of 15 or 30 min ischemia followed by 3 h reperfusion were evaluated in PARS knockout and wild-type mice. Significant protection against histological damage, neutrophil infiltration, and mucosal barrier failure (evaluated by the mucosal-to-serosal FD4 clearance of everted ileal sacs incubated ex vivo) was noted in PARS knockout mice, who also showed reduced alterations in remote organs, as shown by lesser lipid peroxidation (malondialdehyde formation) and neutrophil infiltration in the lung and liver. In conclusion, PARS plays a crucial role in mediating intestinal injury and dysfunction in the early and late phases of mesenteric reperfusion. Pharmacological inhibition of PARS may be a novel approach to protect tissues from reperfusion-related damage.
Mots-clé
Animals
Arterial Occlusive Diseases/complications/physiopathology
Chemotaxis, Leukocyte
DNA Damage
Energy Metabolism
Enzyme Induction
Enzyme Inhibitors/pharmacology
Ileum/metabolism
Intestinal Mucosa/*enzymology/physiopathology
Ischemia/*enzymology/physiopathology
Lipid Peroxidation/drug effects
Liver/pathology
Lung/pathology
Male
Mesenteric Artery, Superior
Mesentery/*blood supply
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophil Infiltration
Neutrophils/immunology
Nitrates/*metabolism
Nitric Oxide Synthase/antagonists & inhibitors
Oxidative Stress
Peroxidase/metabolism
Poly(ADP-ribose) Polymerases/deficiency/genetics/*physiology
Rats
Rats, Wistar
Reperfusion Injury/enzymology
omega-N-Methylarginine/pharmacology
Pubmed
Web of science
Création de la notice
24/01/2008 18:00
Dernière modification de la notice
20/08/2019 14:00