Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia

Details

Serval ID
serval:BIB_22B904A979EA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia
Journal
Shock
Author(s)
Liaudet  L., Szabo  A., Soriano  F. G., Zingarelli  B., Szabo  C., Salzman  A. L.
ISSN
1073-2322 (Print)
Publication state
Published
Issued date
08/2000
Volume
14
Number
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
Abstract
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.
Keywords
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
Create date
24/01/2008 17:00
Last modification date
20/08/2019 13:00
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