COX-2/sEH Dual Inhibitor PTUPB Alleviates CCl 4 -Induced Liver Fibrosis and Portal Hypertension.

Zhifeng Zhao,Yongyang Bao,Xiaoliang Qi,Chihao Zhang,Bruce D Hammock,Haizhong Huo,Sung Hee Hwang,Lei Zheng,Hongjie Li,Meng Luo,Jiayun Lin,Xiaolou Lou

doi:10.3389/fmed.2021.761517

Abstract

Background: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl) -benzenesulfonamide (PTUPB), a dual cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) inhibitor, was found to alleviate renal, pulmonary fibrosis and liver injury. However, few is known about the effect of PTUPB on liver cirrhosis. In this study, we aimed to explore the role of PTUPB in liver cirrhosis and portal hypertension (PHT).Method: Rat liver cirrhosis model was established via subcutaneous injection of carbon tetrachloride (CCl4) for 16 weeks. The experimental group received oral administration of PTUPB (10 mg/kg) for 4 weeks. We subsequently analyzed portal pressure (PP), liver fibrosis, inflammation, angiogenesis, and intra- or extrahepatic vascular remodeling. Additionally, network pharmacology was used to investigate the possible mechanisms of PTUPB in live fibrosis.Results: CCl4 exposure induced liver fibrosis, inflammation, angiogenesis, vascular remodeling and PHT, and PTUPB alleviated these changes. PTUPB decreased PP from 17.50 ± 4.65 to 6.37 ± 1.40 mmHg, reduced collagen deposition and profibrotic factor. PTUPB alleviated the inflammation and bile duct proliferation, as indicated by decrease in serum interleukin-6 (IL-6), liver cytokeratin 19 (CK-19), transaminase, and macrophage infiltration. PTUPB also restored vessel wall thickness of superior mesenteric arteries (SMA) and inhibited intra- or extrahepatic angiogenesis and vascular remodeling via vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), etc. Moreover, PTUPB induced sinusoidal vasodilation by upregulating endothelial nitric oxide synthase (eNOS) and GTP-cyclohydrolase 1 (GCH1). In enrichment analysis, PTUPB engaged in multiple biological functions related to cirrhosis, including blood pressure, tissue remodeling, immunological inflammation, macrophage activation, and fibroblast proliferation. Additionally, PTUPB suppressed hepatic expression of sEH, COX-2, and transforming growth factor-β (TGF-β).Conclusion: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)- benzenesulfonamide ameliorated liver fibrosis and PHT by inhibiting fibrotic deposition, inflammation, angiogenesis, sinusoidal, and SMA remodeling. The molecular mechanism may be mediated via the downregulation of the sEH/COX-2/TGF-β.

Highlights

As a prevalent and challenging illness, liver cirrhosis is characterized by abnormal buildup of hepatic extracellular matrix (ECM) as a result of inflammation or damage [1]
As a dual COX-2/soluble epoxide hydrolase (sEH) inhibitor, we evaluated the inhibitory effect of PTUPB on COX-2/sEH pathways and proinflammatory cytokine TGF-β
Our results showed that PTUPB treatment enhanced the thickness of the superior mesenteric arteries (SMA) wall, improved vascular remodeling, and decreased inflammatory markers including von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), and CD68

Summary

Introduction

As a prevalent and challenging illness, liver cirrhosis is characterized by abnormal buildup of hepatic extracellular matrix (ECM) as a result of inflammation or damage [1]. The ARA can be metabolized and transformed via three pathways: cyclooxygenase (COX), cytochrome P450 (CYP450), and lipoxygenase (LOX). COX and CYP450 pathways are most strongly associated with liver cirrhosis [2]. As a biomarker of inflammation, immune system, and cell proliferation, COX-2 was deeply involved in the progression and deterioration of liver cirrhosis [3]. The CYP450 pathway performed a variety of activities, including antiinflammatory, antihypertension, and antifibrosis, mostly via the epoxyeicosatrienoic acids (EETs) [4,5,6]. EETs are often catalyzed by soluble epoxide hydrolase (sEH) into the less biologically active metabolite in stress situations such as hypertension [7, 8]. The biological activities of ARA pathways depend primarily on COX-2 and sEH

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