Sleep Deprivation Aggravated Lipopolysaccharide/D-galactosamine-induced Acute Liver Injury By Suppressing Melatonin Production

Objective: Accumulating evidence suggests patients with severe hepatic injury usually have some sleep problems such as long sleep onset latency,short sleep duration,but the effects of sleep disturbance on liver injury remain unclear.In the present study,the potential effects of sleep deprivation(SD)on acute liver injury induced by lipopolysaccharide(LPS)/D-galactosamine(D-Gal)and the underlying mechanisms have been investigated.Methods: Male BALB/c mice of 18-22 g weight were intraperitoneally injected with LPS(10 μg/kg)/D-gal(700 mg/kg)to induce acute liver injury.To determine the effects of SD on acute liver injury,we deprivated sleep of mice by using a modified multiple platform water bath for 3 days.The degree of liver injury was detected by aminotransferase determination,histopathology and survival rate analysis,tumor necrosis factor α(TNF-α)and melatonin(MT)were measured by enzyme-linked immunosorbent assay(ELISA).In addition,hepatocyte apoptosis was determined by caspase activity measurement and terminal deoxynucleotidyl transferase d UTP nick end labeling(TUNEL)assay.MT is secreted mainly by the pineal gland of the brain and can be released into the periphery to play biological roles.It has functions of regulating circadian rhythm,improving sleep and anti-inflammatory.To verify the role of MT in LPS/D-Gal induced liver injury,MT was injected intraperitoneally 30 min before LPS/ D-gal exposure to assess the degree of liver injury,inflammatory response,and hepatocyte apoptosis.To investigate the role of MT reduction caused by SD in aggravating liver injury,we injected MT intraperitoneally into acute liver injury model mice during SD for three days to detect the degree of liver injury,inflammatory response and hepatocyte apoptosis.Results: SD increased plasma glutamic-pyruvic transaminase(ALT)、 glutamic oxalacetic transaminase(AST),TUNEL-positive hepatocytes,histological abnormalities and mortality rates in mice with LPS/D-Gal treatment.SD also promoted LPS/D-Gal-induced production of TNF-α and upregulated hepatic caspase-8,caspase-9,and caspase-3activities in LPS/D-Gal-exposed mice.In addition,SD signifcantly decreased MT contents in plasma of mice with acute liver injury.What’s more,MT content was also reduced in the LPS/ D-gal group.To investigate the effect of MT on LPS/ D-Gal-induced acute injury,we conducted MT intervention in model mice and observed that MT inhibited LPS/ D-Gal-induced elevation of ALT activity,TUNEL-positive hepatocyte number,up-regulation of caspase-3 activity and TNF-αproduction,and improved morphological abnormalities.Mice in SD+LPS/D-Gal group were supplemented with MT,and the results showed that MT restrained SD-promoted elevation of mortality and ALT in LPS/D-Gal mice,reduced TNF-α production,suppressed,alleviated histological abnormalities of LPS/D-Gal mice.In addition,MT reduced caspase-3 activity and decreased the number of TUNEL-positive hepatocytes of LPS/D-Gal mice subjected to SD.Conclusion: Our data suggested that SD exacerbated LPS/D-Gal-induced liver injury via decreasing melatonin production.