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

Lucas Liaudet, Andrea Szabó, Francisco Garcia Soriano, Basilia Zingarelli, Csaba Szabo, Andrew L. Salzman

Research output: Contribution to journalArticle

75 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)134-141
Number of pages8
JournalShock
Volume14
Issue number2
StatePublished - Aug 2000
Externally publishedYes

Fingerprint

Poly Adenosine Diphosphate Ribose
Ligases
Reperfusion
Neutrophil Infiltration
Peroxynitrous Acid
Reperfusion Injury
Knockout Mice
Mesenteric Ischemia
DNA Breaks
Superior Mesenteric Artery
Niacinamide
Dextrans
Malondialdehyde
Nitric Oxide Synthase
NAD
Lipid Peroxidation
Peroxidase
Intestines
Glutathione
Ischemia

Keywords

  • 3-aminobenzamide
  • Genetic ablation
  • Intestine
  • Knockout
  • Neutrophil
  • Nicotinamide
  • Nitric oxide
  • Peroxynitrite
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Critical Care and Intensive Care Medicine

Cite this

Liaudet, L., Szabó, A., Soriano, F. G., Zingarelli, B., Szabo, C., & Salzman, A. L. (2000). Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia. Shock, 14(2), 134-141.

Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia. / Liaudet, Lucas; Szabó, Andrea; Soriano, Francisco Garcia; Zingarelli, Basilia; Szabo, Csaba; Salzman, Andrew L.

In: Shock, Vol. 14, No. 2, 08.2000, p. 134-141.

Research output: Contribution to journalArticle

Liaudet, L, Szabó, A, Soriano, FG, Zingarelli, B, Szabo, C & Salzman, AL 2000, 'Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia', Shock, vol. 14, no. 2, pp. 134-141.
Liaudet L, Szabó A, Soriano FG, Zingarelli B, Szabo C, Salzman AL. Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia. Shock. 2000 Aug;14(2):134-141.
Liaudet, Lucas ; Szabó, Andrea ; Soriano, Francisco Garcia ; Zingarelli, Basilia ; Szabo, Csaba ; Salzman, Andrew L. / Poly (ADP-ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia. In: Shock. 2000 ; Vol. 14, No. 2. pp. 134-141.
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AU - Szabo, Csaba

AU - Salzman, Andrew L.

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AB - 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.

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