Abstract
High alcohol intake results in the accumulation of non-oxidative ethanol metabolites such as fatty acid ethyl esters (FAEEs) in the pancreas. High FAEE concentrations mediate pancreatic acinar cell injury and are associated with alcoholic pancreatitis. Treatment with ethanol and the fatty acid palmitoleic acid (EtOH/POA) increased the levels of palmitoleic acid ethyl ester and induced zymogen activation and cytokine expression in pancreatic acinar cells. EtOH/POA induces nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated reactive oxygen species (ROS) production and pancreatic acinar cell injury. Lycopene, a bright-red carotenoid, is a potent antioxidant due to its high number of conjugated double bands. This study aimed to investigate whether lycopene inhibits the EtOH/POA-induced increase in ROS production, zymogen activation, and expression of the inflammatory cytokine IL-6 in EtOH/POA-stimulated pancreatic acinar AR42J cells. EtOH/POA increased the ROS levels, NADPH oxidase and NF-κB activities, zymogen activation, IL-6 expression, and mitochondrial dysfunction, which were inhibited by lycopene. The antioxidant N-acetylcysteine and NADPH oxidase 1 inhibitor ML171 suppressed the EtOH/POA-induced increases in ROS production, NF-κB activation, zymogen activation, and IL-6 expression. Therefore, lycopene inhibits EtOH/POA-induced mitochondrial dysfunction, zymogen activation, and IL-6 expression by suppressing NADPH oxidase-mediated ROS production in pancreatic acinar cells.
Highlights
Acute pancreatitis is an unpredictable and potentially lethal disease, characterized by a local and systemic inflammatory response [1]
ML171 and NAC decreased mRNA expression and protein levels of IL-6 in EtOH/POA-treated cells (Figure 7C,D). These results suggest that EtOH/POA-induced zymogen activation and IL-6 expression is induced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated reactive oxygen species (ROS) production in AR42J cells
We previously showed that ROS mediate NF-κB activation and the expression of inflammatory cytokine IL-6 in cerulein-stimulated pancreatic acinar cells [26]
Summary
Acute pancreatitis is an unpredictable and potentially lethal disease, characterized by a local and systemic inflammatory response [1]. Most patients present with mild acute pancreatitis, which is self-limiting and usually resolves within 1 week. 20% of patients develop moderate or severe acute pancreatitis, with necrosis of the pancreatic or peripancreatic tissue or organ failure, or both, and a substantial mortality rate of 20–40% [2]. Despite improvements in treatment and critical care, severe acute pancreatitis is still associated with high mortality rates. The three most common causes of acute pancreatitis are gallstone/biliary related, alcohol related, and idiopathic. Biliary pathology was estimated to be 28–45% of the cases while alcohol accounted for 19–41% of the cases [2,3]
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