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

Area of Science:

• Biomedical Science
• Physiology
• Pathology

Background:

• Peroxynitrite-induced DNA strand breaks activate poly (ADP-ribose) synthetase (PARS).
• PARS activation leads to cellular energy depletion and organ dysfunction.
• The role of PARS in intestinal response to mesenteric ischemia-reperfusion injury is not fully understood.

Purpose of the Study:

• To investigate the role of PARS activation in the inflammatory and functional response of the intestine to mesenteric ischemia-reperfusion injury.
• To evaluate the therapeutic potential of PARS inhibition in mitigating reperfusion-related damage.

Main Methods:

• Rats and PARS knockout mice were subjected to mesenteric artery occlusion and reperfusion.
• PARS activity was measured using radiolabeled NAD+ incorporation.
• Histological damage, mucosal hyperpermeability (FD4), neutrophil infiltration (myeloperoxidase), and lipid peroxidation (malondialdehyde) were assessed.
• Pharmacological inhibitors of nitric oxide synthase and PARS were used.

Main Results:

• Increased PARS activity was observed in rat intestinal mucosa post-reperfusion.
• PARS inhibition significantly reduced mucosal damage, hyperpermeability, and neutrophil infiltration.
• PARS knockout mice showed significant protection against histological damage, barrier dysfunction, and remote organ injury.
• Inhibition of peroxynitrite production also ameliorated the injury.

Conclusions:

• PARS plays a critical role in mediating intestinal injury and dysfunction during both early and late phases of mesenteric reperfusion.
• Pharmacological inhibition of PARS offers a potential therapeutic strategy to protect tissues from reperfusion injury.
• Targeting PARS may reduce systemic organ damage following ischemic events.