Elsevier

Clinica Chimica Acta

Volume 506, July 2020, Pages 196-203
Clinica Chimica Acta

Review
COX-2 in liver fibrosis

https://doi.org/10.1016/j.cca.2020.03.024Get rights and content

Highlights

  • A recent progress on COX-2-related signaling pathways is summarized.

  • The mechanism relies on COX-2 in hepatic fibrosis, including hepatic inflammation, autophagy, which is described.

  • The potential role of COX-2 on cell senescence is proposed.

Abstract

As a vital inducible sensor, cyclooxygenase-2 (COX-2) plays an important role in the progress of hepatic fibrogenesis. Activation of hepatic stellate cells (HSCs) in the liver can significantly accelerate the onset and development of liver fibrosis. COX-2 overexpression triggers inflammation that is an important inducer in hepatic fibrosis. Increasing evidence indicates that COX-2 is involved in the main pathogenesis of liver fibrosis, such as inflammation, apoptosis, and cell senescence. Moreover, COX-2 expression is altered in patients and animal models with non-alcoholic fatty liver disease or cirrhosis. These findings suggest that COX-2 has a broad and critical role in the development of liver fibrosis. In this review, we summarize the latest advances in the regulation and signal transduction of COX-2 and its impact on liver fibrosis.

Introduction

Liver fibrosis is a pathological outcome of diverse chronic liver diseases such as non-alcoholic steatohepatitis, hepatitis C infection, autoimmune liver disease, and liver cancer, causing it to be one of the leading causes of morbidity and mortality worldwide. Although researchers have made various efforts to solve this perplexing problem, the situation has yet to improve as expected. Currently, the activation of hepatic stellate cells (HSCs) and the deposition of extracellular matrix (ECM) around the sinusoidal cell layer in the Disse are believed to be closely related to the occurrence and progression of liver fibrosis [1]. Other related factors include inflammation, autophagy, apoptosis, and cell senescence. Cyclooxygenases (COX) plays a key role in prostaglandin E2 (PGE2) synthesis from arachidonic acid. COX has three isomers: COX-1, COX-2, and COX-3. COX-1 is predominantly involved in maintaining the structure and homeostasis of the cell. COX-2 is a potent enzyme that can initiate inflammation and promote the synthesis of prostaglandins after being stimulated by various inflammatory factors such as cytokines and bacteria [2]. However, increasing evidence shows that COX-2 has more functions, including negatively regulating autophagic mark proteins such as LC2, Beclin, ATG-5, and p62, as well as inhibiting cell senescence [3], [4], [5]. These data suggest that the extensive roles of COX-2 may play a crucial part in the initiation and progression of liver fibrosis. To explore a novel insight into possible impacts of COX-2 during hepatic fibrogenesis, we summarize the latest progress of COX-2 and its related signaling pathways and propose a novel strategy for preventing and treating liver diseases through targeting COX-2.

Section snippets

Characteristics and structures

COX, the prostaglandin-endoperoxide synthase, catalyzes the conversion of arachidonic acid to prostaglandins (PGs), thromboxane, and prostacyclin. COX has three isomers, including COX-1, COX-2, and COX-3 [6]. COX-1 is constitutively and ubiquitously expressed in the intestinal tract, kidneys, and blood placket to synthesize PGs and thromboxane. COX-2 is mainly upregulated by cytokines and growth factors, enhancing the production of prostaglandins during inflammatory states [7], [8]. For

Regulation

COX is normally low in several tissues and cells. However, it can be induced by numerous factors such as inflammation and hepatic injury [21], [22]. For example, tumor promoter PMA and cytokine IL-1 induce COX-2 transcription in vascular endothelial cells, synovial fibroblasts [23]. In synovial fibroblasts, the induction of COX-2 is completely suppressed by the anti-inflammatory steroid dexamethasone [24]. Moreover, the expression of COX-2 in hepatic is related to the development of

The roles of COX-2 in the pathophysiological process of liver fibrosis

Liver fibrosis is a common pathophysiological process in liver diseases. As a rate-limiting enzyme, COX-2 catalyzes the conversion of arachidonic acid into inflammatory prostaglandins and thromboxane [7]. Recently, Qin et al. reported that the inhibition of cell division cycle 7-related protein kinase (CDC7) can specifically induce TP53 gene mutation in liver cancer cells, causing various defects such as cell senescence [53]. A follow-up drug screening showed that a mTOR inhibitor can further

Discussion

COX-2 is an important molecule in the progress of hepatic fibrosis and may play a critical role in liver inflammation, autophagy, and cell senescence. COX-2 can also alter the characteristics of autophagy and cell senescence, and its expression may represent cell senescence phenotype. Upon induction, COX-2 may mediate certain fibrosis phenotype factors characterized by an aberrant inflammatory response, preventing the acceleration of hepatic fibrosis. However, the function of COX-2 in autophagy

Declaration of Competing Interest

The authors claimed that they do not have any information about conflicts of interest in the manuscript.

Acknowledgment

The authors gratefully acknowledge the financial support from the Program for Science and Technology Department of Hunan Province (2018DK51707).

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