AICAR attenuates organ injury and inflammatory response after intestinal ischemia and reperfusion.

Abstract

Intestinal ischemia and reperfusion (I/R) is encountered in various clinical conditions and contributes to multiorgan failure and mortality as high as 60% to 80%. Intestinal I/R not only injures the intestine, but affects remote organs such as the lung leading to acute lung injury. The development of novel and effective therapies for intestinal I/R are critical for the improvement of patient outcome. AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside) is a cell-permeable compound that has been shown to possess antiinflammatory effects. The objective is to determine that treatment with AICAR attenuates intestinal I/R injury and subsequent acute lung injury (ALI). Male Sprague Dawley rats (275 to 325 g) underwent intestinal I/R injury with blockage of the superior mesenteric artery for 90 min and subsequent reperfusion. At the initiation of reperfusion, vehicle or AICAR (30 mg/kg BW) was given intravenously (IV) for 30 min. At 4 h after reperfusion, blood and tissues were collected for further analyses. Treatment with AICAR significantly decreased the gut damage score and the water content, indicating improvement in histological integrity. The treatment also attenuated tissue injury and proinflammatory cytokines, and reduced bacterial translocation to the gut. AICAR administration after intestinal I/R maintained lung integrity, attenuated neutrophil chemotaxis and infiltration to the lungs and decreased lung levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Inflammatory mediators, lung-inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, were decreased in the lungs and lung apoptosis was significantly reduced after AICAR treatment. These data indicate that AICAR could be developed as an effective and novel therapeutic for intestinal I/R and subsequent ALI.

• Authors: Juan-Pablo Idrovo, Weng-Lang Yang, Asha Jacob, Monowar Aziz, Jeffrey Nicastro, Gene F Coppa, Ping Wang
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 20 Pg. 676-83 (Mar 19 2015) ISSN: 1528-3658 [Electronic] England
• PMID: 25611433 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Inflammatory Agents
• Interleukin-6
• Ribonucleotides
• Tumor Necrosis Factor-alpha
• Aminoimidazole Carboxamide
• L-Lactate Dehydrogenase
• Peroxidase
• Aspartate Aminotransferases
• Alanine Transaminase
• AICA ribonucleotide

Topics

• Acute Lung Injury (drug therapy, metabolism, pathology)
• Alanine Transaminase (blood)
• Aminoimidazole Carboxamide (analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Aspartate Aminotransferases (blood)
• Bacterial Load
• Interleukin-6 (blood, metabolism)
• Intestinal Mucosa (metabolism)
• Intestines (blood supply, drug effects, pathology)
• L-Lactate Dehydrogenase (blood)
• Lung (drug effects, metabolism, pathology)
• Lymph Nodes (microbiology)
• Male
• Mice
• Peroxidase (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, metabolism, pathology)
• Ribonucleotides (pharmacology, therapeutic use)
• Tumor Necrosis Factor-alpha (blood, metabolism)