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

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

  • Oxid Med Cell Longev. 2022 Apr 25;2022:5759626. doi: 10.1155/2022/5759626.
Chen-Yu Zhang 1 2 Xin-Xin Guan 1 Zhuo-Hui Song 3 Hui-Ling Jiang 1 Yu-Biao Liu 1 Ping Chen 2 4 Jia-Xi Duan 2 4 Yong Zhou 1
Affiliations

Affiliations

  • 1 Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, Hunan 410078, China.
  • 2 Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
  • 3 Department of Physiology, Changzhi Medical College, Changzhi, Shanxi 046000, China.
  • 4 Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China.
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. In vitro 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)-β1-induced EMT.

Results: PTUPB treatment reversed the increase of mesenchymal marker molecule α-smooth muscle actin (α-SMA) and the loss of epithelial marker molecule E-cadherin in lung tissue of PF mice. In vitro, COX-2 and sEH protein levels were increased in TGF-β1-treated alveolar epithelial cells (AECs). PTUPB decreased the expression of α-SMA and restored the expression of E-cadherin in TGF-β1-treated AECs, accompanied by reduced migration and collagen synthesis. Moreover, PTUPB attenuated TGF-β1-Smad2/3 pathway activation in AECs via Nrf2 antioxidant cascade.

Conclusion: PTUPB inhibits EMT in AECs via Nrf2-mediated inhibition of the TGF-β1-Smad2/3 pathway, which holds great promise for the clinical treatment of PF.

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