Abstract
Background: Intestinal ischemia/reperfusion injury (IRI) remains a clinical event that contributes to high morbidity and mortality rates. Intestinal epithelium is exposed to histological and vascular changes following tissue ischemia. Prolyl endopeptidase (PREP), involved in inflammatory responses, could be targeted for recovery from the permanent consequences following intestinal ischemia. Our aim was to investigate the role of PREP inhibitor KYP-2047 in tissue damage, angiogenesis, and endothelial barrier permeability after intestinal IRI in mice. Methods: KYP-2047 treatments were performed 5 min prior to intestinal damage. Intestinal IRI was induced in mice by clamping the superior mesenteric artery and the celiac trunk for 30 min, followed by 1 h of reperfusion. Results: PREP inhibition by KYP-2047 treatment reduced intestinal IR-induced histological damage and neutrophil accumulation, limiting inflammation through decrease of NF-ĸB nuclear translocation and fibrotic processes. KYP-2047 treatment restored barrier permeability and structural alteration following intestinal IRI, attenuating neovascular processes compromised by ischemia/reperfusion. Additionally, loss of epithelial cells during intestinal ischemia occurring by apoptosis was limited by KYP-2047 treatment, which showed strong effects counteracting apoptosis and DNA damage. Conclusions: These findings provide the first evidence that PREP inhibition through KYP-2047 inhibitor use could be a validate strategy for resolving alterations of intestinal epithelium the pathophysiology of intestinal disease.
Highlights
Mesenteric ischemia (MI) is a severe pathological event associated with a varied number of diseases such as vessel obstruction, hernias, and septic shock often resulting in morbidity and death [1]
We aimed to investigate the effects of Prolyl endopeptidase (PREP) inhibition through the small-molecule KYP-2047 inhibitor used to fight angiogenesis and apoptosis in a mouse model of intestinal ischemia/reperfusion injury (IRI)
Histopathological analyses of intestines confirmed that the intestinal IRI group (Figure 1 panel B, magnifications B1) resulted in significant mucosal injury compared to the sham group
Summary
Mesenteric ischemia (MI) is a severe pathological event associated with a varied number of diseases such as vessel obstruction, hernias, and septic shock often resulting in morbidity and death [1]. The II refers to a complex consequence including loss of organ-specific activity, alteration of gut microbiota, tissue necrosis, and the release of proinflammatory cytokines (interleukin 1β [IL-1β] and tumor necrosis factor α [TNF-α]) and reactive oxygen species (ROS). This cascade is driven by the nuclear factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Results: PREP inhibition by KYP-2047 treatment reduced intestinal IR-induced histological damage and neutrophil accumulation, limiting inflammation through decrease of NF-kB nuclear translocation and fibrotic processes. KYP-2047 treatment restored barrier permeability and structural alteration following intestinal IRI, attenuating neovascular processes compromised by ischemia/reperfusion
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