Pancreatic duct obstruction itself induces expression of alpha smooth muscle actin in pancreatic stellate cells.
ABSTRACT Pancreatic stellate cells (PSCs) are thought to be responsible for pancreatic fibrosis. Although fibrosis is a major characteristic of chronic pancreatitis (CP) induced by pancreatic duct obstruction, it is unclear whether pancreatic duct obstruction itself activates PSCs.
To test the hypothesis that pancreatic duct obstruction activates PSCs, clinical and experimental analyses were performed using alpha smooth muscle actin (alpha-SMA) as a marker of their activation. In clinical analysis, surgical specimens from the patients with pancreatic cancer or cancer of the papilla Vater were classified into two groups with or without duct obstruction. alpha-SMA expression was examined on these specimens, and the difference between two groups was evaluated. In animal experiment, duct ligation-induced pancreatitis was developed in rats by ligating the secondary pancreatic duct in duodenal segment, and the expression of alpha-SMA was examined.
In clinical analysis, the specimens from the pancreas with duct obstruction (14 cases) expressed alpha-SMA significantly stronger than those from the pancreas without duct obstruction (7 cases). All specimens in the former expressed alpha-SMA, but 4 specimens from the latter did not at all (P < 0.05). In animal experiment, alpha-SMA expression was detected 7 days after the ligation and was increased on the 10th day.
We can assume that pancreatic duct obstruction itself activates PSCs. This mechanism may play roles in the development of CP from multiple origins.
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ABSTRACT: Heparan sulphate is known to have various functions in the animal body, including surveillance of tissue integrity. Administered intraperitoneally, it induces a systemic inflammatory response syndrome and when given locally in the pancreas it initiates a protective inflammatory response. The aim of the present study was to investigate the underlying mechanisms behind cell recruitment following intra-ductal infusion of heparan sulphate. Rats were subjected to intraductal-infusion of heparan sulphate, lipopolysaccharide and phosphate buffered saline into the pancreas. Pancreatic tissue was harvested 1, 3, 6, 9 or 48 hours after infusion and stained immunohistochemically for myeloperoxidase, ED-1, CINC-1 and MCP-1, as well as using eosin hematoxylin staining. Furthermore, MPO activity and MCP-1 and CINC-1 concentrations of tissue homogenates were measured. All differences were analyzed statistically using the Mann-Whitney U-test. During HS infusion, a rapid influx of macrophages/monocytes, as visualized as ED-1 positive cells, was seen reaching a maximum at 6 hours. After 48 hours, the same levels of ED-1 positive cells were noted in the pancreatic tissue, but with different location and morphology. Increased neutrophil numbers of heparan sulphate treated animals compared to control could be detected only 9 hours after infusion. The number of neutrophils was lower than the number of ED-1 positive cells. On the contrary, LPS infusion caused increased neutrophil numbers to a larger extent than heparan sulphate. Furthermore, this accumulation of neutrophils preceded the infiltration of ED-1 positive cells. Chemokine expression correlates very well to the cell infiltrate. MCP-1 was evident in the ductal cells of both groups early on. MCP-1 preceded monocyte infiltration in both groups, while the CINC-1 increase was only noticeable in the LPS group. Our data suggest that heparan and LPS both induce host defense reactions, though by using different mechanisms of cell-recruitment. This implies that the etiology of pancreatic inflammation may influence how the subsequent events will develop.Journal of Inflammation 05/2010; 7:24. DOI:10.1186/1476-9255-7-24 · 2.22 Impact Factor
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ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis. To date patient outcomes have not improved principally due to the limited number of patients suitable for surgical resections and the radiation and chemotherapy resistance of these tumours. In the last decade, a failure of conventional therapies has forced researchers to re-examine the environment of PDAC. The tumour environment has been demonstrated to consist of an abundance of stroma containing many cells but predominantly pancreatic stellate cells (PSCs). Recent research has focused on understanding the interaction between PSCs and PDAC cells in vitro and in vivo. It is believed that the interaction between these cells is responsible for supporting tumour growth, invasion and metastasis and creating the barrier to delivery of chemotherapeutics. Novel approaches which focus on the interactions between PDAC and PSCs which sustain the tumour microenvironment may achieve significant patient benefits. This manuscript reviews the current evidence regarding PSCs, their interaction with PDAC cells and the potential implication this may have for future therapies.European journal of cancer (Oxford, England: 1990) 08/2014; 50(15). DOI:10.1016/j.ejca.2014.06.021 · 4.82 Impact Factor
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ABSTRACT: Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed.Fibrogenesis & Tissue Repair 12/2011; 4(1):26. DOI:10.1186/1755-1536-4-26