ReviewCOX-2 in 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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