Pathogenic mechanisms of pancreatitis

Abstract

Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for pancreatic pathogenesis.

Keywords: Janus kinase/signal transducers and activators; Mitogen-activated protein kinases; Pancreatic stellate cells; Pancreatitis; Transforming growth factor-β/SMAD.

Figure 1

Structure of pancreas. A: The pancreas is a leaf-like structure and has two types of cells: Exocrine cells, that include acinar pancreatic duct cells, and endocrine cells, that include islets of Langerhans; B: The inflammatory process in the pancreas promotes fibrosis (scarring of tissue), calcifications or stones, and dilated pancreatic duct.

Figure 2

Pathogenesis of pancreatitis. Diagrammatic representation of the onset of pancreatitis by damaged pancreatic acinar cells which in turn activates quiescent pancreatic stellate cells (PSCs) to become activated PSCs and promote subsequent fibrosis of pancreas. TNF-α: Tumor necrosis factor-α; TGF-β: Transforming growth factor-β; PDGF: Platelet-derived growth factor; IL: Interleukin.

Figure 3

Various signaling pathways involved in the development of pancreatic fibrosis. Diagrammatic representation of various molecular signaling pathways which are involved in the development of pancreatic fibrosis. TGF-β: Transforming growth factor-β; PDGF: Platelet-derived growth factor; IL: Interleukin; MAPK: Mitogen-activated protein kinase; PI3K: Phosphatidylinositol 3 kinase; AP-1: Activator protein-1; NFκB: Nuclear factor kappa B.