Abstract
Acute liver injury (ALI) causes life-threatening clinical problem, and its underlying etiology includes inflammation and apoptosis. An adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), exhibits anti-inflammatory and anti-apoptotic effects by inhibiting the secretion of pro-inflammatory cytokines. In the current study, the protective effect of PDRN against carbon tetrachloride (CCl4)-induced ALI was investigated using mice. For the induction of ALI, mice received intraperitoneal injection of CCl4 twice over seven days. Mice from the PDRN-treated groups received an intraperitoneal injection of 200 μL saline containing PDRN (8 mg/kg), once a day for seven days, starting on day 1 after the first CCl4 injection. In order to confirm that the action of PDRN occurs through the adenosine A2A receptor, 8 mg/kg 3,7-dimethyl-1-propargylxanthine (DMPX), an adenosine A2A receptor antagonist, was treated with PDRN. Administration of CCl4 impaired liver tissue and increased the liver index and histopathologic score. The expression of pro-inflammatory cytokines was increased, and apoptosis was induced by the administration of CCl4. Administration of CCl4 activated nuclear factor-kappa B (NF-κB) and facilitated phosphorylation of signaling factors in mitogen-activated protein kinase (MAPK). In contrast, PDRN treatment suppressed the secretion of pro-inflammatory cytokines and inhibited apoptosis. PDRN treatment inactivated NF-κB and suppressed phosphorylation of signaling factors in MAPK. As a result, liver index and histopathologic score were reduced by PDRN treatment. When PDRN was treated with DMPX, the anti-inflammatory and anti-apoptotic effect of PDRN disappeared. Therefore, PDRN can be used as an effective therapeutic agent for acute liver damage.
Highlights
The liver is responsible for many physiological functions, including metabolism
In this study, we evaluated the effect of PDRN on carbon tetrachloride (CCl4)-induced Acute liver injury (ALI) focusing on the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway
Intraperitoneal administration of CCl4 increased the expression of cytochrome P450 2E1 (CYP2E1) and uncoupling protein 2 (UCP2) in liver tissue compared to the control group (p < 0.05)
Summary
The liver is responsible for many physiological functions, including metabolism. Excessive hepatocyte apoptosis is likely to contribute to ALI by causing liver dysfunction [7]. T cells, and macrophages are mobilized during ALI, and liver-resident macrophages act as a factor contributing to liver damage by mass production of cytokines in response to inflammatory stimuli [8]. These inflammatory cells secrete pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and these pro-inflammatory cytokines play a role in promoting ALI progression. During ALI progression, various damaging factors contribute to the inflammatory response and promote liver cell apoptosis, thereby increasing liver tissue damage [9,10]
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