Abstract
The haemorrhagic disease virus (RHDV) is a non‐cultivable virus that promotes in rabbits an acute disease which accomplishes many characteristics of an animal model of fulminant hepatic failure (FHF). Beneficial effects of melatonin have been reported in RHDV‐infected rabbits. This study investigated whether protection against viral‐derived liver injury by melatonin is associated with modulation of mitophagy, innate immunity and clock signalling. Rabbits were experimentally infected with 2 × 104 haemagglutination units of a RHDV isolate and killed at 18, 24 and 30 hours after infection (hpi). Melatonin (20 mg/kg body weight ip) was administered at 0, 12 and 24 hpi. RHDV infection induced mitophagy, with the presence of a high number of mitophagosomes in hepatocytes and increased expression of mitophagy genes. Greater expression of main innate immune intermediaries and inflammasome components was also found in livers with RHDV‐induced FHF. Both mitophagy and innate immunity activation was significantly hindered by melatonin. FHF induction also elicited an early dysregulation in clock signalling, and melatonin was able to prevent such circadian disruption. Our study discloses novel molecular routes contributing to RHDV‐induced damage progression and supports the potential of melatonin as a promising therapeutic option in human FHF.
Highlights
Acute liver injury induced by rabbit haemorrhagic disease virus (RHDV) infection has been previously demonstrated in this animal model by our group, and blood chemistry and immunohistochemical data have shown a damage reduction by melatonin administration.[5,10]
Our findings suggest that melatonin could modulate crucial mechanisms which contribute to severe hepatic damage in a RHDV-induced model of Fulminant hepatic failure (FHF).[5,10,12,13,14,34]
Our results demonstrated an early augmented expression of PTEN-induced putative kinase protein 1 (PINK1) and PARKIN, mostly marked since 24 hpi, which was accompanied by an increase in the number and content of mitophagy vesicles in liver tissue form RHDVinfected rabbits
Summary
Fulminant hepatic failure (FHF) is a life-threatening clinical pathology, induced by drugs, toxins and viral hepatitis, with a complex set of mechanisms responsible for the impairment of liver function.[1,2,3] In the absence of suitable animal models to better study causes and treatments of liver damage, specially of viral origin, our group developed an FHF model by rabbit haemorrhagic disease virus (RHDV) infection which complies many requirements of human FHF and reproduces the most representative histologic and biochemical parameters and clinical symptoms of the human disease.[4,5,6,7,8] The RHDV virus is a member of the viral family Caliciviridae, which has no possibility to be cultured, and RHDV infection results in a mortality rate higher than 90% within 2-3 days because of the massive liver damage in adult rabbits,[9] supplying a valuable platform to evaluate cell-damaging mechanisms in severe human FHF, as well as the therapeutic potential of hepatoprotective therapies in this condition. Melatonin is a product of the pineal gland which has proved to regulate a high number of molecular mechanisms, including endoplasmic reticulum stress, apoptosis and autophagy, involved in the progression of hepatic damage.[1,15,25,26,27,28,29,30,31,32,33] In rabbits infected with RHDV, melatonin reduces liver injury by a combination of antioxidant, anti-inflammatory and anti-apoptotic effects, being able to modulate sphingolipid metabolism.[5,10,13,34] Beneficial effects of melatonin on liver diseases such as fibrosis and hepatocarcinoma are closely related to the biological clock machinery,[28,30] and recent studies found a likely REV-ERBα implication on inflammasome activation and mitochondria homeostasis during severe hepatic damage.[16,23,35]. Data obtained reveal new molecular mechanisms accounting for the protective effect of the indole in this viral animal model of FHF and support the potential of melatonin as an antiviral agent
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