N‐acetylcysteine induces beneficial changes in the acinar cell cycle progression in the course of acute pancreatitis

Abstract

Oxygen free radicals (OFR) are produced in the course of acute pancreatitis (AP). In addition to injurious oxidative effects, they are also involved in the regulation of cell growth. The aim of the present study was to examine the relationship between the effectiveness of N-acetyl-l-cysteine (NAC) to prevent the generation of OFR and the changes in the cell-cycle pattern of acinar cells in the course of AP induced in rats by pancreatic duct obstruction (PDO). NAC (50 mg/kg) was administered 1 h before and 1 h after PDO. Flow-cytometric measurement of OFR generation in acinar cells was carried out using dihydrorhodamine as fluorescent dye. Plasma amylase activity, pancreatic glutathione (GSH) content and TNF-alpha plasma levels were also measured. The distribution of acinar cells throughout the different cell-cycle phases was analysed at different AP stages by flow cytometry using propidium iodide staining. NAC administration reduced the depletion of pancreatic GSH content and prevented OFR generation in acinar cells of rats with PDO-induced acute pancreatitis. As a result, AP became less severe as reflected by the significant improvement of hyper-amylasaemia and maintenance of plasma TNF-alpha levels at values not significantly different from controls were found. NAC administration inhibited progression of cell-cycle phases, maintaining acinar cells in quiescent state at early PDO times. The protection from oxidative damage by NAC treatment during early AP, allows the pancreatic cell to enter S-phase actively at later stages, thereby allowing acinar cells to proliferate and preventing the pancreatic atrophy provoked by PDO-induced AP. The results provide evidence that OFR play a critical role in the progression of acinar cell-cycle phases. Prevention of OFR generation of acinar cells in rats with PDO-induced AP through NAC treatment, not only protects pancreas from oxidative damage but also promotes beneficial changes in the cell cycle progression which reduce the risk of pancreatic atrophy.

Ultrastructural clues for the protective effect of ascorbic acid and N-acetylcysteine against oxidative damage on caerulein-induced pancreatitis

“…In our study, the tissue GSH level was higher in the group administered ascorbic acid + NAC than in the AP group. It is reported that NAC administration reduces the depletion of pancreatic GSH content and prevents OFR generation in acinar cells of rats with pancreatic duct obstruction-induced AP [40,41] .…”

N-Acetylcysteine Reduces the Pro-Oxidant and Inflammatory Responses during Pancreatitis and Pancreas Tumorigenesis

“…As glutathione is depleted during pancreatitis, we questioned the usefulness of the thiol-containing compound, NAC, on pancreatic redox homeostasis and inflammation severity. Early studies have reported a positive antioxidant effect of NAC during pancreatitis in WT mice and human cells from patients with redox disorders [31][32][33][34][35][36]. However, the exact impact of NAC on pancreatic inflammation in a Kras G12D background is still not clearly elucidated.…”