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

Shingo Matsuo, Andrew Chaung, Deanna Liou, Ping Wang, Weng Lang Yang

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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 endlabeling- 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.

Original languageEnglish (US)
Pages (from-to)G283-G292
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume315
Issue number2
DOIs
StatePublished - Aug 9 2018
Externally publishedYes

Keywords

  • Gut ischemia-reperfusion
  • Inflammation
  • Inhibitor
  • Organ injury
  • Ubiquitination

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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