一种新型 miRNA 模拟物可减轻肝缺血/再灌注后的器官损伤。

A novel miRNA mimic attenuates organ injury after hepatic ischemia/reperfusion.

机构信息

From the Departments of (T.B., A.J., M.K., V.P., G.F.C., M.A., P.W.) Surgery and Molecular Medicine (A.J., M.A., P.W.), Zucker School of Medicine at Hofstra/Northwell; and Center for Immunology and Inflammation (T.B., A.J., M.K., M.A., P.W.), The Feinstein Institutes for Medical Research, Manhasset, New York.

出版信息

J Trauma Acute Care Surg. 2023 May 1;94(5):702-709. doi: 10.1097/TA.0000000000003877. Epub 2023 Feb 2.

DOI:10.1097/TA.0000000000003877

PMID:36726195

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10133008/

Abstract

INTRODUCTION

Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel mediator of inflammation and tissue injury. It has been shown that miRNA 130b-3p acts as an endogenous inhibitor of eCIRP. Because RNA mimics are unstable after in vivo administration, we have chemically engineered miRNA 130b-3p mimic (named PS-OMe miR130) to improve its stability by protection from nuclease activity. We hypothesize that PS-OMe miR130 reduces eCIRP-mediated injury and inflammation in a murine model of hepatic ischemia/reperfusion (I/R), a model of sterile inflammation.

METHODS

Adult male mice underwent 70% hepatic ischemia for 60 minutes and 24-hour reperfusion. At the start of reperfusion, mice were treated intravenously with vehicle (phosphate-buffered saline) or PS-OMe miR130. Blood and liver tissue were collected after 24 hours for biochemical analysis. Apoptosis in the liver tissue was determined by transferase dUTP nick-end labeling assay.

RESULTS

After hepatic I/R, organ injury markers including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase significantly decreased after PS-OMe miR130 treatment. Furthermore, histological analysis of liver sections demonstrated significantly less injury in PS-OMe miR130 treatment mice versus vehicle mice. In addition, tumor necrosis factor α mRNA, interleukin-1β mRNA, and neutrophil infiltration (myeloperoxidase activity and granulocyte receptor 1 immunohistochemistry) were significantly attenuated after PS-OMe miR130 treatment. Finally, apoptosis significantly decreased in liver tissue after treatment.

CONCLUSION

PS-OMe miR130 decreases eCIRP-mediated injury and inflammation in a murine model of hepatic I/R.

摘要

简介

细胞外冷诱导 RNA 结合蛋白（eCIRP）是一种新型炎症和组织损伤介质。研究表明，miRNA 130b-3p 作为 eCIRP 的内源性抑制剂发挥作用。由于体内给药后 RNA 模拟物不稳定，我们通过保护其免受核酸酶活性的影响，对 miRNA 130b-3p 模拟物（命名为 PS-OMe miR130）进行了化学修饰，以提高其稳定性。我们假设 PS-OMe miR130 可减少肝缺血再灌注（I/R）小鼠模型（无菌性炎症模型）中 eCIRP 介导的损伤和炎症。

方法

成年雄性小鼠接受 70%肝缺血 60 分钟和 24 小时再灌注。再灌注开始时，小鼠经静脉给予载体（磷酸盐缓冲盐水）或 PS-OMe miR130。24 小时后采集血液和肝组织进行生化分析。通过 TUNEL 测定法检测肝组织中的细胞凋亡。

结果

肝 I/R 后，PS-OMe miR130 处理组的天冬氨酸转氨酶、丙氨酸转氨酶和乳酸脱氢酶等器官损伤标志物明显降低。此外，PS-OMe miR130 处理组小鼠肝组织切片的组织学分析显示损伤明显减少。此外，PS-OMe miR130 处理组肿瘤坏死因子-α mRNA、白细胞介素-1β mRNA 和中性粒细胞浸润（髓过氧化物酶活性和粒细胞受体 1 免疫组化）明显减弱。最后，肝组织中的细胞凋亡明显减少。