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COX-2/sEH 双重抑制剂 PTUPB 通过抑制 TGF-β1/Smad 信号转导减轻肺泡上皮细胞上皮-间充质转化。Nrf2 介导的抑制作用。

COX-2/sEH Dual Inhibitor PTUPB Attenuates Epithelial-Mesenchymal Transformation of Alveolar Epithelial Cells Nrf2-Mediated Inhibition of TGF-1/Smad Signaling.

机构信息

Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan 410078, China.

Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.

出版信息

Oxid Med Cell Longev. 2022 Apr 25;2022:5759626. doi: 10.1155/2022/5759626. eCollection 2022.

DOI:10.1155/2022/5759626
PMID:35509835
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9060975/
Abstract

BACKGROUND

Arachidonic acid (ARA) metabolites are involved in the pathogenesis of epithelial-mesenchymal transformation (EMT). However, the role of ARA metabolism in the progression of EMT during pulmonary fibrosis (PF) has not been fully elucidated. The purpose of this study was to investigate the role of cytochrome P450 oxidase (CYP)/soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) metabolic disorders of ARA in EMT during PF.

METHODS

A signal intratracheal injection of bleomycin (BLM) was given to induce PF in C57BL/6 J mice. A COX-2/sEH dual inhibitor PTUPB was used to establish the function of CYPs/COX-2 dysregulation to EMT in PF mice. experiments, murine alveolar epithelial cells (MLE12) and human alveolar epithelial cells (A549) were used to explore the roles and mechanisms of PTUPB on transforming growth factor (TGF)-1-induced EMT.

RESULTS

PTUPB treatment reversed the increase of mesenchymal marker molecule -smooth muscle actin (-SMA) and the loss of epithelial marker molecule E-cadherin in lung tissue of PF mice. , COX-2 and sEH protein levels were increased in TGF-1-treated alveolar epithelial cells (AECs). PTUPB decreased the expression of -SMA and restored the expression of E-cadherin in TGF-1-treated AECs, accompanied by reduced migration and collagen synthesis. Moreover, PTUPB attenuated TGF-1-Smad2/3 pathway activation in AECs Nrf2 antioxidant cascade.

CONCLUSION

PTUPB inhibits EMT in AECs Nrf2-mediated inhibition of the TGF-1-Smad2/3 pathway, which holds great promise for the clinical treatment of PF.

摘要

背景

花生四烯酸（ARA）代谢物参与上皮间质转化（EMT）的发病机制。然而，ARA 代谢在肺纤维化（PF）过程中 EMT 的进展中的作用尚未完全阐明。本研究旨在探讨 CYP/可溶性环氧化物水解酶（sEH）和环氧合酶-2（COX-2）代谢异常在 PF 过程中 EMT 中 ARA 的作用。

方法

通过气管内注射博来霉素（BLM）诱导 C57BL/6J 小鼠 PF。使用 COX-2/sEH 双重抑制剂 PTUPB 建立 CYP/COX-2 失调对 PF 小鼠 EMT 的功能。进行实验，使用鼠肺泡上皮细胞（MLE12）和人肺泡上皮细胞（A549）探索 PTUPB 对 TGF-β1 诱导的 EMT 的作用及其机制。

结果

PTUPB 治疗逆转了 PF 小鼠肺组织中间充质标记分子-α平滑肌肌动蛋白（-SMA）的增加和上皮标记分子 E-钙粘蛋白的丢失。此外，COX-2 和 sEH 蛋白水平在 TGF-β1 处理的肺泡上皮细胞（AEC）中增加。PTUPB 降低了 -SMA 的表达并恢复了 TGF-β1 处理的 AEC 中 E-钙粘蛋白的表达，同时减少了迁移和胶原合成。此外，PTUPB 减弱了 TGF-β1-Smad2/3 通路在 AEC 中的激活，同时激活了 Nrf2 抗氧化级联反应。

结论

PTUPB 抑制 AEC 中的 EMT 及其通过 Nrf2 抑制 TGF-β1-Smad2/3 通路，这为 PF 的临床治疗提供了广阔的前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/9cbca6f1d602/OMCL2022-5759626.009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/8f4e592ecfc1/OMCL2022-5759626.001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/2ce5e0a20501/OMCL2022-5759626.008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/9cbca6f1d602/OMCL2022-5759626.009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/8f4e592ecfc1/OMCL2022-5759626.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/489b54f31c20/OMCL2022-5759626.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/483f411f4bd8/OMCL2022-5759626.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/f28f270fb00b/OMCL2022-5759626.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/cbf337e1b72b/OMCL2022-5759626.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/fc4541f4f27a/OMCL2022-5759626.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/4dcdd467911c/OMCL2022-5759626.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/2ce5e0a20501/OMCL2022-5759626.008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84b5/9060975/9cbca6f1d602/OMCL2022-5759626.009.jpg

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