The etiology of chronic pancreatitis varies greatly as demonstrated in the TIGAR-O classification. However, due to the lack of correlation and reproducibility between the etiologic factors and the presentation of the disease, it is presumed that individual sensitivity such as genetic predisposition would play an important role in its pathogenesis. Although our understanding on the pathophysiology of chronic pancreatitis is still far from being adequate, we are gaining more insights on its underlying mechanism through active researches related to pancreatic stellate cells, and molecular/genetic studies. Since the clinical manifestations of chronic pancreatitis show significant variation according to its cause, stages of the disease, and presence of local complications, controversy still remains regarding the natural course of chronic pancreatitis and warrants further study. At present, it is generally agreed that acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis lie on the same spectrum of the disease.
Genetic Predisposition to Disease ; Pancreatic Stellate Cells ; Pancreatitis ; Pancreatitis, Chronic

Chronic pancreatitis is an ongoing inflammatory disorder characterized by irreversible destruction of the pancreas associated with disabling chronic pain and permanent loss of exocrine and endocrine function. Fibrosis and loss of acinar cell mass in the pancreas are characteristic findings in chronic pancreatitis, and pancreatic fibrosis is suggested to contribute to the irreversibility of the disease Over the past several decades, several theories have emerged to explain the pathogenesis and evolution of pancreatitis. These models provide conceptual frameworks that are not mutually exclusive, but at times are mutually contradictory. The role of pancreatic fibrogenesis in response to various forms of pancreatic injury and the relationship of fibrogenesis in response to the progression from acute to chronic form is emphasized within the sentinel acute pancreatitis event (SAPE) model of chronic pancreatitis. Studies on pancreatic fibrogenesis have been given new impetus, largely because of the identification and characterization of stellate-shaped cells in the pancreas. In the normal pancreas, pancreatic stellate cells (PSC) exist in a quiescent state. However in pancreatic injury, the PSCs are activated so that they exhibit increased proliferation, transformation onto myofibroblast-like cells and synthesize increased amounts of the extracellular matrix proteins that form fibrous tissues. Therefore, the PSCs have a central role in pancreatic fibrogenesis. Over the past several decades, the pathogenesis of chronic pancreatitis has been studied. However, the pathogenesis of chronic pancreatitis is unclear. Therefore, further studies would be needed to clarify the pathogenesis of chronic pancreatitis..
Acinar Cells ; Chronic Pain ; Extracellular Matrix Proteins ; Fibrosis ; Pancreas ; Pancreatic Stellate Cells ; Pancreatitis ; Pancreatitis, Chronic*

Acute pancreatitis is an inflammatory disease characterized by interstitial edema, inflammatory cell infiltration, and acinar cell necrosis, depending on its severity. Regardless of the extent of tissue injury, acute pancreatitis is a completely reversible process with evident normal tissue architecture after recovery. Its pathogenic mechanism has been known to be closely related to intracellular digestive enzyme activation. In contrast to acute pancreatitis, chronic pancreatitis is characterized by irreversible tissue damage such as acinar cell atrophy and pancreatic fibrosis that results in exocrine and endocrine insufficiency. Recently, many studies of chronic pancreatitis have been prompted by the discovery of the pancreatic stellate cell, which has been identified and distinguished as the key effector cell of pancreatic fibrosis. However, investigations into the pathogenesis and treatment of pancreatitis face many obstacles because of its anatomical location and disparate clinical course. Due to these difficulties, most of our knowledge on pancreatitis is based on research conducted using experimental models of pancreatitis. In this review, several experimental models of pancreatitis will be discussed in terms of technique, advantages, and limitations.
Acinar Cells ; Animals ; Atrophy ; Edema ; Enzyme Activation ; Fibrosis ; Models, Theoretical* ; Necrosis ; Pancreatic Stellate Cells ; Pancreatitis* ; Pancreatitis, Chronic

Animals ; Cells, Cultured ; Collagen Type I ; Gene Expression ; Mice ; Pancreatic Stellate Cells ; RNA, Small Interfering/genetics* ; Receptor, Notch3 ; Signal Transduction

BACKGROUND/AIMS: High-fat diets contribute to pancreatic fibrogenesis, but the pathogenesis remains unclear. This study investigated the role of nuclear factor kappa B (NF-kappaB) in high-fat diet-induced pancreatic fibrosis in rats. METHODS: Male Wistar rats were fed a high-fat diet or standard normal chow for 20 weeks. Pancreatic fibrosis was determined by Sirius red staining. Immunohistochemical staining, reverse transcription-polymerase chain reaction and Western blotting were used to identify NF-kappaB-associated genes or protein expressions. RESULTS: Inflammation, fat deposition, pancreatic stellate cell activation and fibrosis were observed in the pancreases of the high-fat diet group. NF-kappaB subunit p65 (NF-kappaB/p65) expression was localized to the nucleus, and intercellular adhesion molecule 1 (ICAM-1) was over-expressed. Pancreatic gene expression levels of NF-kappaB/p65, ICAM-1 and tumor necrosis factor alpha were all elevated significantly in rats fed a high-fat diet compared with control rats. Western blotting also revealed significantly increased levels of ICAM-1 and nuclear NF-kappaB/p65 in rats fed high-fat diets comparison with control rats. CONCLUSIONS: NF-kappaB is involved in high-fat diet-related pancreatic fibrosis.
Animals ; Blotting, Western ; Diet, High-Fat ; Fibrosis ; Gene Expression ; Humans ; Inflammation ; Intercellular Adhesion Molecule-1 ; Male ; NF-kappa B ; Pancreas ; Pancreatic Stellate Cells ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha

BACKGROUND/AIMS: Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPARgamma) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPARgamma agonists separately inhibit pancreatic stellate cell (PaSC) activation. We studied the effects of a combination of both types of drugs on activated PaSCs via platelet-derived growth factor (PDGF), which has not previously been reported. The present study was performed to elucidate the underlying mechanisms of these effects by focusing on the impact of the signaling associated with cell-cycle progression. METHODS: Primary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantified using the BrdU method, and cell-cycle analysis was performed using a fluorescent activated cell sorter. The protein expression levels of smooth muscle actin (SMA), extracellular signal-regulated kinase (ERK), and a cell cycle machinery protein (p27Kip1) were investigated using Western blot analysis. RESULTS: Simvastatin reversed the effects of PDGF on cell proliferation in a dose-dependent manner. The combination of a low concentration of simvastatin (1 mM) and troglitazone (10 mM) synergistically reversed the effects of PDGF on cell proliferation but had no effect on cell viability. The expression of a-SMA was markedly attenuated by combining the two drugs, which blocked the cell cycle beyond the G0/G1 phase by reducing the levels of phosphorylated ERK and reversed the expression of p27Kip1 interrupted by PDGF. CONCLUSIONS: Simvastatin and troglitazone synergistically inhibited cell proliferation in activated PaSCs by blocking the cell cycle beyond the G0/G1 phase. This inhibition was due to the synergistic modulation of the ERK pathway and the cell cycle machinery protein p27Kip1.
Actins ; Acyl Coenzyme A ; Animals ; Apoptosis ; Blotting, Western ; Bromodeoxyuridine ; Cell Cycle ; Cell Proliferation ; Cell Survival ; Chromans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Ligands ; MAP Kinase Signaling System ; Muscle, Smooth ; Oxidoreductases ; Pancreatic Stellate Cells ; Phosphotransferases ; Platelet-Derived Growth Factor ; PPAR gamma ; Rats ; Simvastatin ; Thiazolidinediones