Inhibition of ubiquitin-activating enzyme protects against organ injury after intestinal ischemia-reperfusion.

Abstract

Intestinal ischemia-reperfusion (I/R) occurs in various clinical settings, such as transplantation, acute mesenteric arterial occlusion, trauma, and shock. I/R injury causes severe systemic inflammation, leading to multiple organ dysfunction associated with high mortality. The ubiquitin proteasome pathway has been indicated in the regulation of inflammation, particularly through the NF-κB signaling pathway. PYR-41 is a small molecular compound that selectively inhibits ubiquitin-activating enzyme E1. A mouse model of intestinal I/R injury by clamping the superior mesenteric artery for 45 min was performed to evaluate the effect of PYR-41 treatment on organ injury and inflammation. PYR-41 was administered intravenously at the beginning of reperfusion. Blood and organ tissues were harvested at 4 h after reperfusion. PYR-41 treatment improved the morphological structure of gut and lung after I/R, as judged by hematoxylin and eosin staining. It also reduced the number of apoptotic terminal deoxynucleotidyl transferase dUTP nick end-labeling-positive cells and caspase-3 activity in the organs. PYR-41 treatment decreased the expression of proinflammatory cytokines IL-6 and IL-1β as well as chemokines keratinocyte chemoattractant and macrophage inflammatory protein-2 in the gut and lung, which leads to inhibition of neutrophils infiltrating into these organs. The serum levels of IL-6, aspartate aminotransferase, and lactate dehydrogenase were reduced by the treatment. The IκB degradation in the gut increased after I/R was inhibited by PYR-41 treatment. Thus, ubiquitination may be a potential therapeutic target for treating patients suffering from intestinal I/R. NEW & NOTEWORTHY Excessive inflammation contributes to organ injury from intestinal ischemia-reperfusion (I/R) in many clinical conditions. NF-κB signaling is very important in regulating inflammatory response. In an experimental model of gut I/R injury, we demonstrate that administration of a pharmacological inhibitor of ubiquitination process attenuates NF-κB activation, leading to reduction of inflammation, tissue damage, and apoptosis in the gut and lungs. Therefore, ubiquitination process may serve as a therapeutic target for treating patients with intestinal I/R injury.

• Authors: Shingo Matsuo, Andrew Chaung, Deanna Liou, Ping Wang, Weng-Lang Yang
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 315 Issue 2 Pg. G283-G292 (08 01 2018) ISSN: 1522-1547 [Electronic] United States
• PMID: 29771572 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 4(4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl)-benzoic acid ethyl ester
• Anti-Inflammatory Agents
• Benzoates
• Furans
• NF-kappa B
• Pyrazoles
• Ubiquitin
• Ubiquitin-Activating Enzymes

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Apoptosis (drug effects)
• Benzoates (pharmacology)
• Disease Models, Animal
• Furans (pharmacology)
• Inflammation (drug therapy, metabolism)
• Intestines (blood supply)
• Mesenteric Ischemia (immunology)
• Mice
• NF-kappa B (metabolism)
• Pyrazoles (pharmacology)
• Reperfusion Injury (drug therapy, immunology)
• Ubiquitin (metabolism)
• Ubiquitin-Activating Enzymes (metabolism)
• Ubiquitination (drug effects)