Oxidative stress and inflammatory signaling in cerulein pancreatitis

Abstract

Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.

Keywords: Cerulein pancreatitis; Inflammatory signaling; Reactive oxygen species.

Figure 1

Scheme of oxidative stress-induced inflammation in cerulein pancreatitis. High dose of cerulein, a cholecystokinin (CCK) analogue, binds to CCK2 receptor and stimulates the activation of NAPH oxidase to produce reactive oxygen species. Reactive oxygen species activate redox-sensitive transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) as well as inflammatory mediators mitogen-activated protein kinases (MAPKs) (mitogen-activated protein kinases) and janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), which in turn induces the expression of cytokines IL-1β, IL-6, IL-8, and TNF-α in pancreas. Induction of cytokines recruits neutrophils and macrophages in the injured pancreatic tissues. Cytokines/chemokines act as a positive feedback loop to up-regulates their own expression. Therefore, cytokines positively regulate the induction of cytokines and pancreatic injuries are amplified. Peroxisome proliferator activated receptor-γ (PPAR-γ) ligands inhibit the activation of JAK2/STAT3 and suppresses inflammatory signaling in pancreas. Antioxidant nutrients and natural compounds reduce the levels of reactive oxygen species and suppress activation of NF-κB, AP-1, MAPKs, and JAK2/STAT3 to inhibit induction of cytokines and pancreatic injuries in experimental pancreatitis (in vitro, in vivo). Some clinical studies show a lack of benefit from antioxidant therapy while others have beneficial effects against acute and chronic pancreatitis by alleviating symptoms and enhancing the cure rate.