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J. Merkord - One of the best experts on this subject based on the ideXlab platform.
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Influence of Selenium Treatment on the Acute Toxicity of Dibutyltin Dichloride in Rats
Pancreatology, 2006Co-Authors: M. Lemke, N. Görl, A. Berg, H. Weber, G. Hennighausen, J. MerkordAbstract:Background/Aims: Dibutyltin Dichloride (DBTC) is an organotin compound used as a model for acute pancreatitis.The aim was to determine the effect of various doses of Na-selenite on
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cytokine mrna levels and lymphocyte infiltration in pancreatic tissue during experimental chronic pancreatitis induced by Dibutyltin Dichloride
Digestive Diseases and Sciences, 2001Co-Authors: Gisela Sparmann, J. Merkord, Stefan Liebe, Stefan Behrend, Hansdieter Kleine, E Graser, Thomas Ritter, Jörg EmmrichAbstract:There is little information available regarding the role of inflammatory cells in the pathogenesis of chronic pancreatitis. Therefore, we analyzed the local cytokine profile and infiltrating lymphocytes in a rat model of chronic pancreatitis. Experimental pancreatitis was induced by a single intravenous application of dibultyltin Dichloride (DBTC). During a time course of two months we observed the mRNA expression of cytokines using competitive RT-PCR. Lymphocytes were characterized by immunohistochemistry, FACS analysis, and the lymphocyte proliferation test. IL-1β, IL-6, IL-5, and IL-10 were immediately up-regulated in the acute phase of disease, while lymphocyte-restricted expression of IL-2, IL-2R, and IFN-γ was only found in the chronic course. Among the infiltrating lymphocytes, CD4+ cells dominated, but during the chronic process there was an increase of CD8+ cells, resulting in a reduced CD4/CD8 ratio. Mitogen-induced activation of isolated mesenteric lymph node cells increased during the chronic inflammation. Our results suggest that in experimental pancreatitis acute inflammatory reactions are followed by a T-lymphocyte-mediated process.
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the course of pancreatic fibrosis induced by Dibutyltin Dichloride dbtc
Annals of the New York Academy of Sciences, 1999Co-Authors: J. Merkord, Gisela Sparmann, Ludwig Jonas, Heike Weber, G. HennighausenAbstract:In summary, in addition to an acute interstitial pancreatitis the organotin compound DBTC induced a pancreatic fibrosis in rats. The course of the pancreatic fibrosis was studied 2-36 weeks after single i.v. treatment of rats with 6 or 8 mg/kg DBTC. The pancreatic fibrosis induced by DBTC differs from other experimental models of acute pancreatitis. Extensive infiltration by mononuclear cells is present in fibrotic areas without pancreatic atrophy or lipomatosis. The presence of chronic inflammatory lesions characterized by the destruction of exocrine parenchyma and fibrosis and in the later stages the endocrine parenchyma, indicate a chronic pancreatitis. In completion of the experimental model of the DBTC-induced acute interstitial pancreatitis in rats, the described late fibrotic effects on rat pancreas may be used as an experimental model of chronic pancreatitis.
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the influence of ethanol on long term effects of Dibutyltin Dichloride dbtc in pancreas and liver of rats
Human & Experimental Toxicology, 1998Co-Authors: J. Merkord, Horst Nizze, Ludwig Jonas, Heike Weber, G. HennighausenAbstract:The present study was done to determine the additional influence of daily ethanol intake (15% in drinking water ad libitum) on long-term toxic effects of a single administration of Dibutyltin Dichloride (DBTC, 8 mg/kg b.w. i.v.) in pancreas and liver of rats. Pathohistological changes in pancreas, bile duct and liver as well as pathobiochemical parameters of pancreatitis (amylase and lipase activity), liver lesions (alkaline phosphatase activity and bilirubin) and fibrosis (hydroxyproline and hyaluronic acid) were measured 1 day and 1 to 24 weeks after DBTC- and DBTC/ethanol administration. DBTC alone induced in rats an acute interstitial pancreatitis as well as acute bile duct and liver lesions in the early experimental phase. Later on, the acute inflammatory processes in pancreas and liver took a chronic course resulting in pancreatic fibrosis and liver cirrhosis. Ethanol increased the toxic effects of DBTC on pancreas and liver during the acute and chronic course. In the acute phase lasting 1 day to 2 weeks, ethanol enhanced the DBTC toxicity on acinar cell and bilio-pancreatic duct epithelium as well as the formation of obstructive ductal plugs by necrotic cell debris. The obstruction and cholestasis in the DBTC/ethanol-group were significantly stronger as in the DBTC-group. The significant increase of hydroxyproline in urine and hyaluronic acid in serum of the DBTC/ethanol treated rats after 12 to 24 weeks was connected with a more severe chronic inflammatory fibrosis in pancreas and liver in comparison to the DBTC-treated group.
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acute interstitial pancreatitis in rats induced by Dibutyltin Dichloride dbtc pathogenesis and natural course of lesions
Pancreas, 1997Co-Authors: J. Merkord, Horst Nizze, Ludwig Jonas, H. Weber, G Kroning, G. HennighausenAbstract:Dibutyltin Dichloride (DBTC; 6 mg/kg body weight, i.v.) induced acute interstitial pancreatitis in rats. The course of the pancreatitis was examined within 28 days by light and electron microscopy as well as by pathobiochemistry (amylase, lipase, alkaline phosphatase, and bilirubin in serum; tin concentration in biliopancreatic juice, tissue, and concretions). The pathogenesis of the DBTC-induced pancreatitis in rats was studied by different experimental designs (in intact animals, after bile duct ligation, after surgical bypass of the bile duct). DBTC caused toxic necrosis of the biliopancreatic duct epithelium, which is then shed into the duct and forms obstructing plugs in the distal common bile duct. Interstitial pancreatitis occurred during the first 4 days, accompanied by significantly increased activities of serum α-amylase and lipase. After 7 days extensive infiltration of the pancreatic interstitium with mononuclear cells was observed. Twenty-eight days after administration of DBTC one-third of the rats showed periductal and interstitial fibrosis as well as an active inflammatory process in the pancreas. The findings suggest a twofold pathogenesis of the DBTC-induced pancreatitis: first, the cytotoxic effects on the biliopancreatic duct epithelium lead to epithelial necrosis with obstruction of the duct, subsequent cholestasis, and interstitial pancreatitis; and second, the hematogenic DBTC effects cause direct injury of pancreatic cells (mitochondrial damage, autophagy, cell necrosis) followed by interstitial edema and inflammation. Both processes lead to this special type of DBTC-induced acute pancreatitis with a tendency to a chronic course, when the obstruction of the duct and cholestasis persist.
G. Hennighausen - One of the best experts on this subject based on the ideXlab platform.
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Influence of Selenium Treatment on the Acute Toxicity of Dibutyltin Dichloride in Rats
Pancreatology, 2006Co-Authors: M. Lemke, N. Görl, A. Berg, H. Weber, G. Hennighausen, J. MerkordAbstract:Background/Aims: Dibutyltin Dichloride (DBTC) is an organotin compound used as a model for acute pancreatitis.The aim was to determine the effect of various doses of Na-selenite on
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the course of pancreatic fibrosis induced by Dibutyltin Dichloride dbtc
Annals of the New York Academy of Sciences, 1999Co-Authors: J. Merkord, Gisela Sparmann, Ludwig Jonas, Heike Weber, G. HennighausenAbstract:In summary, in addition to an acute interstitial pancreatitis the organotin compound DBTC induced a pancreatic fibrosis in rats. The course of the pancreatic fibrosis was studied 2-36 weeks after single i.v. treatment of rats with 6 or 8 mg/kg DBTC. The pancreatic fibrosis induced by DBTC differs from other experimental models of acute pancreatitis. Extensive infiltration by mononuclear cells is present in fibrotic areas without pancreatic atrophy or lipomatosis. The presence of chronic inflammatory lesions characterized by the destruction of exocrine parenchyma and fibrosis and in the later stages the endocrine parenchyma, indicate a chronic pancreatitis. In completion of the experimental model of the DBTC-induced acute interstitial pancreatitis in rats, the described late fibrotic effects on rat pancreas may be used as an experimental model of chronic pancreatitis.
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the influence of ethanol on long term effects of Dibutyltin Dichloride dbtc in pancreas and liver of rats
Human & Experimental Toxicology, 1998Co-Authors: J. Merkord, Horst Nizze, Ludwig Jonas, Heike Weber, G. HennighausenAbstract:The present study was done to determine the additional influence of daily ethanol intake (15% in drinking water ad libitum) on long-term toxic effects of a single administration of Dibutyltin Dichloride (DBTC, 8 mg/kg b.w. i.v.) in pancreas and liver of rats. Pathohistological changes in pancreas, bile duct and liver as well as pathobiochemical parameters of pancreatitis (amylase and lipase activity), liver lesions (alkaline phosphatase activity and bilirubin) and fibrosis (hydroxyproline and hyaluronic acid) were measured 1 day and 1 to 24 weeks after DBTC- and DBTC/ethanol administration. DBTC alone induced in rats an acute interstitial pancreatitis as well as acute bile duct and liver lesions in the early experimental phase. Later on, the acute inflammatory processes in pancreas and liver took a chronic course resulting in pancreatic fibrosis and liver cirrhosis. Ethanol increased the toxic effects of DBTC on pancreas and liver during the acute and chronic course. In the acute phase lasting 1 day to 2 weeks, ethanol enhanced the DBTC toxicity on acinar cell and bilio-pancreatic duct epithelium as well as the formation of obstructive ductal plugs by necrotic cell debris. The obstruction and cholestasis in the DBTC/ethanol-group were significantly stronger as in the DBTC-group. The significant increase of hydroxyproline in urine and hyaluronic acid in serum of the DBTC/ethanol treated rats after 12 to 24 weeks was connected with a more severe chronic inflammatory fibrosis in pancreas and liver in comparison to the DBTC-treated group.
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acute interstitial pancreatitis in rats induced by Dibutyltin Dichloride dbtc pathogenesis and natural course of lesions
Pancreas, 1997Co-Authors: J. Merkord, Horst Nizze, Ludwig Jonas, H. Weber, G Kroning, G. HennighausenAbstract:Dibutyltin Dichloride (DBTC; 6 mg/kg body weight, i.v.) induced acute interstitial pancreatitis in rats. The course of the pancreatitis was examined within 28 days by light and electron microscopy as well as by pathobiochemistry (amylase, lipase, alkaline phosphatase, and bilirubin in serum; tin concentration in biliopancreatic juice, tissue, and concretions). The pathogenesis of the DBTC-induced pancreatitis in rats was studied by different experimental designs (in intact animals, after bile duct ligation, after surgical bypass of the bile duct). DBTC caused toxic necrosis of the biliopancreatic duct epithelium, which is then shed into the duct and forms obstructing plugs in the distal common bile duct. Interstitial pancreatitis occurred during the first 4 days, accompanied by significantly increased activities of serum α-amylase and lipase. After 7 days extensive infiltration of the pancreatic interstitium with mononuclear cells was observed. Twenty-eight days after administration of DBTC one-third of the rats showed periductal and interstitial fibrosis as well as an active inflammatory process in the pancreas. The findings suggest a twofold pathogenesis of the DBTC-induced pancreatitis: first, the cytotoxic effects on the biliopancreatic duct epithelium lead to epithelial necrosis with obstruction of the duct, subsequent cholestasis, and interstitial pancreatitis; and second, the hematogenic DBTC effects cause direct injury of pancreatic cells (mitochondrial damage, autophagy, cell necrosis) followed by interstitial edema and inflammation. Both processes lead to this special type of DBTC-induced acute pancreatitis with a tendency to a chronic course, when the obstruction of the duct and cholestasis persist.
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morphological lesions of pancreas and bile ducts in rats induced by Dibutyltin Dichloride
Archives of Toxicology, 1991Co-Authors: J. Merkord, L Jonas, G. HennighausenAbstract:Dialkyltin compounds have been widely used as biocides, catalysts and plastic stabilizers (Kimmel et al 1977). DBTC is the final product of the stabilization reaction of polyvinyl chloride resins and it is used as a catalyst for formation of polyurethane foam (Piver 1973).
Tetsuhide Ito - One of the best experts on this subject based on the ideXlab platform.
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a sustained prostacyclin analog ono 1301 attenuates pancreatic fibrosis in experimental chronic pancreatitis induced by Dibutyltin Dichloride in rats
Pancreatology, 2014Co-Authors: Yusuke Niina, Tetsuhide Ito, Takamasa Oono, Taichi Nakamura, Nao Fujimori, Hisato Igarashi, Yoshiki Sakai, Ryoichi TakayanagiAbstract:Abstract Background ONO-1301, a novel sustained-release prostacyclin agonist, has an anti-fibrotic effect on the lungs, heart, and kidneys that is partly associated with the induction of hepatocyte growth factor (HGF). This study examined the anti-fibrotic effect of ONO-1301 on chronic pancreatitis (CP) progression. Methods CP was induced in rats in vivo by Dibutyltin Dichloride (DBTC). Seven days after DBTC injection (day 7), a slow-release form of ONO-1301 (10 mg/kg; ONO-1301–treated group) or vehicle (DBTC-treated group) was injected. On days 14 and 28, we evaluated the histopathological CP score and mRNA expressions of HGF, cytokines, and collagen in the pancreas by real-time RT-PCR. In vitro , monocytes and pancreatic stellate cells (PSCs) were isolated from normal rat spleen and pancreas, respectively. The cytokine and collagen expressions of monocytes and PSCs were detected by real-time RT-PCR, and PSCs proliferation was examined by BrdU assay. Results Histopathological CP scores in vivo improved in the ONO-1301–treated group compared to the DBTC-treated group, particularly inflammatory cell infiltration on day 14 and interstitial fibrosis on day 28. HGF mRNA increased significantly after ONO-1301 administration, whereas IL-1β, TNF-α, TGF-β, MCP-1, and collagen mRNA decreased significantly. Cytokine expression in monocytes was suppressed in vitro not only by HGF, but also ONO-1301 alone. However, neither ONO-1301 nor HGF affected the proliferation, or cytokine or collagen expression of PSCs. Conclusions ONO-1301 suppresses pancreatic fibrosis in the DBTC-induced CP model by inhibiting monocyte activity not only with induction of HGF but also by ONO-1301 itself.
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is 741 attenuates local migration of monocytes and subsequent pancreatic fibrosis in experimental chronic pancreatitis induced by Dibutyltin Dichloride in rats
Pancreas, 2007Co-Authors: Toyoma Kaku, Junya Gibo, Tetsuhide Ito, Takamasa Oono, Haifeng Zhao, Ken Kawabe, Ryoichi TakayanagiAbstract:OBJECTIVES Chronic pancreatitis consists of excessive leukocyte infiltration and fibrosis. IS-741 has been reported to be an antiinflammatory drug through an inhibitory action on cell adhesion. In this study, we investigated whether IS-741 could inhibit the progression of pancreatic fibrosis through monocyte infiltration. Moreover, we investigated the effect of IS-741 on rat pancreatic stellate cells (PSCs). METHODS Chronic pancreatitis was induced by Dibutyltin Dichloride in rats. From days 7 to 28 after Dibutyltin Dichloride application, IS-741 or distilled water was administered. At days 14 and 28, histological [hematoxylin-eosin stain and immunostain for ED1 and [alpha] smooth muscle actin (alpha-SMA)] and biochemical evaluations (intrapancreatic amylase, protein, cytokines, chemokines, and alpha-SMA) were performed. In vitro, rat PSCs were incubated with cytokine, chemokine, and growth factor simultaneously with IS-741, and their proliferation and activation were examined. RESULTS Histologically, IS-741 inhibited pancreatic fibrosis and decreased the number of ED1- and [alpha]-SMA-positive cells. The intrapancreatic expression of cytokines, chemokine, and [alpha]-SMA were also decreased. In vitro, IS-741 has no direct effect on the proliferation, alpha-SMA expression, and collagen synthesis of PSCs. CONCLUSIONS These results suggest that IS-741 suppressed macrophage infiltration and subsequent pancreatic fibrosis and that the infiltration of monocytes into pancreas is essential for pancreatic fibrosis.
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anti monocyte chemoattractant protein 1 gene therapy attenuates experimental chronic pancreatitis induced by Dibutyltin Dichloride in rats
Gut, 2005Co-Authors: Haifeng Zhao, Junya Gibo, Tetsuhide Ito, Yoshiyuki Arita, Takamasa Oono, Toyoma Kaku, Ken Kawabe, Qingwei Zhao, Makoto Usui, Kensuke EgashiraAbstract:Background: Monocyte chemoattractant protein 1 (MCP-1) is a member of the C-C chemokine family and exerts strong chemoattractant activity in monocytes, macrophages, and lymphocytes. Rat pancreatic fibrosis induced by Dibutyltin Dichloride (DBTC) is considered to be an appropriate chronic pancreatitis model histologically and enzymatically, as has demonstrated in a previous study. Aim: We examined the effect of human dominant negative inhibitor of MCP-1 (mutant MCP-1) on progression of chronic pancreatitis induced by DBTC in a rat model. Methods: We used the experimental model of chronic pancreatitis induced by DBTC in rats. Mutant MCP-1 or empty plasmid at a dose of 50 µg/body weight was administrated into rat thigh muscles on days 4, 11, and 18 after administration of DBTC. On days 14 and 28, we evaluated the effect of mutant MCP-1 morphologically and biochemically. Results: The mutant MCP-1 treated group inhibited early pancreatic inflammation and later pancreatic fibrosis histologically, and showed a decrease in serum MCP-1 concentration, intrapancreatic hydroxyproline, α-smooth muscle actin, and an increase in intrapancreatic amylase and protein content compared with the empty plasmid treated group. The mutant MCP-1 group also inhibited intrapancreatic mRNA expression of cytokines and chemokines. Conclusions: : Our findings suggest that monocyte/macrophage recruitment and the systemic MCP-1 signal pathway contribute to progression of chronic pancreatitis, and that blockade of MCP-1 may suppress the development of pancreatic fibrosis.
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The role of monocyte chemoattractant protein-1 in experimental chronic pancreatitis model induced by Dibutyltin Dichloride in rats.
Pancreas, 2002Co-Authors: Masanobu Inoue, Yoshifumi Ino, Junya Gibo, Tetsuhide Ito, Terumasa Hisano, Yoshiyuki Arita, Hajime NawataAbstract:IntroductionRecently, Dibutyltin Dichloride (DBTC) was reported to induce pancreatic fibrosis within 28 days in rats, but it is not clear that the induced condition should be considered chronic pancreatitis.Aim and MethodologyThe aim of this study was to clarify whether the pancreatic fibrosis induc
Gisela Sparmann - One of the best experts on this subject based on the ideXlab platform.
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immunologic characterization of acute pancreatitis in rats induced by Dibutyltin Dichloride dbtc
Pancreas, 2003Co-Authors: Steffi Hense, Gisela Sparmann, Stefan Liebe, Heike Weber, Jörg EmmrichAbstract:There is little information available regarding the role of inflammatory cells and cytokines in the pancreatic tissue during acute interstitial pancreatitis. The single intravenous application of Dibutyltin Dichloride (DBTC) induces a pancreatitis in rats with a dosage dependent course. We analyzed the infiltrating leukocytes and the cytokine expression profile in the experimental model of DBTC-initiated mild interstitial pancreatitis during a time course of 4 weeks. Macrophages dominated among the infiltrating inflammatory cells detected by immunohistochemistry. The expression of IL-1beta, IL-10, and TGFbeta1 was shown to be elevated 24 hours after onset of pancreatitis reaching a maximum during the first week. Positive immunostaining of IL-1beta, IL-10, or TGFbeta1 was not restricted to infiltrating leukocytes but was found to various degrees in pancreatic cells. Transcripts of collagen type 1 reached high levels in the first week, but were down regulated thereafter. There was no significant expression of IL-2, IL-2 receptor, IL-4, TNFalpha, or IFNgamma. Our data show that the experimental interstitial pancreatitis was characterized by macrophage infiltration accompanied by elevated cytokine expression that lasted longer than the visible morphologic lesions. These inflammatory processes might create the environment that makes the pancreas more susceptible to further damaging effects.
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cytokine mrna levels and lymphocyte infiltration in pancreatic tissue during experimental chronic pancreatitis induced by Dibutyltin Dichloride
Digestive Diseases and Sciences, 2001Co-Authors: Gisela Sparmann, J. Merkord, Stefan Liebe, Stefan Behrend, Hansdieter Kleine, E Graser, Thomas Ritter, Jörg EmmrichAbstract:There is little information available regarding the role of inflammatory cells in the pathogenesis of chronic pancreatitis. Therefore, we analyzed the local cytokine profile and infiltrating lymphocytes in a rat model of chronic pancreatitis. Experimental pancreatitis was induced by a single intravenous application of dibultyltin Dichloride (DBTC). During a time course of two months we observed the mRNA expression of cytokines using competitive RT-PCR. Lymphocytes were characterized by immunohistochemistry, FACS analysis, and the lymphocyte proliferation test. IL-1β, IL-6, IL-5, and IL-10 were immediately up-regulated in the acute phase of disease, while lymphocyte-restricted expression of IL-2, IL-2R, and IFN-γ was only found in the chronic course. Among the infiltrating lymphocytes, CD4+ cells dominated, but during the chronic process there was an increase of CD8+ cells, resulting in a reduced CD4/CD8 ratio. Mitogen-induced activation of isolated mesenteric lymph node cells increased during the chronic inflammation. Our results suggest that in experimental pancreatitis acute inflammatory reactions are followed by a T-lymphocyte-mediated process.
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the course of pancreatic fibrosis induced by Dibutyltin Dichloride dbtc
Annals of the New York Academy of Sciences, 1999Co-Authors: J. Merkord, Gisela Sparmann, Ludwig Jonas, Heike Weber, G. HennighausenAbstract:In summary, in addition to an acute interstitial pancreatitis the organotin compound DBTC induced a pancreatic fibrosis in rats. The course of the pancreatic fibrosis was studied 2-36 weeks after single i.v. treatment of rats with 6 or 8 mg/kg DBTC. The pancreatic fibrosis induced by DBTC differs from other experimental models of acute pancreatitis. Extensive infiltration by mononuclear cells is present in fibrotic areas without pancreatic atrophy or lipomatosis. The presence of chronic inflammatory lesions characterized by the destruction of exocrine parenchyma and fibrosis and in the later stages the endocrine parenchyma, indicate a chronic pancreatitis. In completion of the experimental model of the DBTC-induced acute interstitial pancreatitis in rats, the described late fibrotic effects on rat pancreas may be used as an experimental model of chronic pancreatitis.
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Pancreatic fibrosis in experimental pancreatitis induced by Dibutyltin Dichloride.
Gastroenterology, 1997Co-Authors: Gisela Sparmann, J. Merkord, A. Jäschke, Horst Nizze, Ludwig Jonas, Matthias Löhr, Stefan Liebe, Jörg EmmrichAbstract:BACKGROUND & AIMS: Regulatory mechanisms in chronic pancreatitis finally resulting in pancreatic fibrosis cannot be studied sufficiently in human pancreas. Results of a new pancreatitis model in rats suitable for investigation of the processes leading to pancreatic fibrosis are presented. METHODS: Experimental pancreatitis was induced by intravenous application of 8 mg/kg body wt Dibutyltin Dichloride. Pancreatitis was characterized by histology, serum parameters, and immunohistochemistry, detecting inflammatory cells. Gene expression of collagen type I and transforming growth factor beta1 was shown by Northern blot analysis. RESULTS: Dibutyltin Dichloride induced an acute edematous pancreatitis within 24 hours. Extensive infiltration with mononuclear cells could be observed after day 7 followed by the development of fibrosis. Parallel to the cell infiltration, an upregulation of messenger RNA-encoding collagen type I and transforming growth factor beta1 could be shown. An active inflammatory process could be shown until the end of the observation period, i.e., 2 months. CONCLUSIONS: The findings suggest that Dibutyltin Dichloride-induced pancreatitis in rats is suitable to study cellular interactions and mediators involved in the development of pancreatic fibrosis. (Gastroenterology 1997 May;112(5):1664-72)
Junya Gibo - One of the best experts on this subject based on the ideXlab platform.
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is 741 attenuates local migration of monocytes and subsequent pancreatic fibrosis in experimental chronic pancreatitis induced by Dibutyltin Dichloride in rats
Pancreas, 2007Co-Authors: Toyoma Kaku, Junya Gibo, Tetsuhide Ito, Takamasa Oono, Haifeng Zhao, Ken Kawabe, Ryoichi TakayanagiAbstract:OBJECTIVES Chronic pancreatitis consists of excessive leukocyte infiltration and fibrosis. IS-741 has been reported to be an antiinflammatory drug through an inhibitory action on cell adhesion. In this study, we investigated whether IS-741 could inhibit the progression of pancreatic fibrosis through monocyte infiltration. Moreover, we investigated the effect of IS-741 on rat pancreatic stellate cells (PSCs). METHODS Chronic pancreatitis was induced by Dibutyltin Dichloride in rats. From days 7 to 28 after Dibutyltin Dichloride application, IS-741 or distilled water was administered. At days 14 and 28, histological [hematoxylin-eosin stain and immunostain for ED1 and [alpha] smooth muscle actin (alpha-SMA)] and biochemical evaluations (intrapancreatic amylase, protein, cytokines, chemokines, and alpha-SMA) were performed. In vitro, rat PSCs were incubated with cytokine, chemokine, and growth factor simultaneously with IS-741, and their proliferation and activation were examined. RESULTS Histologically, IS-741 inhibited pancreatic fibrosis and decreased the number of ED1- and [alpha]-SMA-positive cells. The intrapancreatic expression of cytokines, chemokine, and [alpha]-SMA were also decreased. In vitro, IS-741 has no direct effect on the proliferation, alpha-SMA expression, and collagen synthesis of PSCs. CONCLUSIONS These results suggest that IS-741 suppressed macrophage infiltration and subsequent pancreatic fibrosis and that the infiltration of monocytes into pancreas is essential for pancreatic fibrosis.
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anti monocyte chemoattractant protein 1 gene therapy attenuates experimental chronic pancreatitis induced by Dibutyltin Dichloride in rats
Gut, 2005Co-Authors: Haifeng Zhao, Junya Gibo, Tetsuhide Ito, Yoshiyuki Arita, Takamasa Oono, Toyoma Kaku, Ken Kawabe, Qingwei Zhao, Makoto Usui, Kensuke EgashiraAbstract:Background: Monocyte chemoattractant protein 1 (MCP-1) is a member of the C-C chemokine family and exerts strong chemoattractant activity in monocytes, macrophages, and lymphocytes. Rat pancreatic fibrosis induced by Dibutyltin Dichloride (DBTC) is considered to be an appropriate chronic pancreatitis model histologically and enzymatically, as has demonstrated in a previous study. Aim: We examined the effect of human dominant negative inhibitor of MCP-1 (mutant MCP-1) on progression of chronic pancreatitis induced by DBTC in a rat model. Methods: We used the experimental model of chronic pancreatitis induced by DBTC in rats. Mutant MCP-1 or empty plasmid at a dose of 50 µg/body weight was administrated into rat thigh muscles on days 4, 11, and 18 after administration of DBTC. On days 14 and 28, we evaluated the effect of mutant MCP-1 morphologically and biochemically. Results: The mutant MCP-1 treated group inhibited early pancreatic inflammation and later pancreatic fibrosis histologically, and showed a decrease in serum MCP-1 concentration, intrapancreatic hydroxyproline, α-smooth muscle actin, and an increase in intrapancreatic amylase and protein content compared with the empty plasmid treated group. The mutant MCP-1 group also inhibited intrapancreatic mRNA expression of cytokines and chemokines. Conclusions: : Our findings suggest that monocyte/macrophage recruitment and the systemic MCP-1 signal pathway contribute to progression of chronic pancreatitis, and that blockade of MCP-1 may suppress the development of pancreatic fibrosis.
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The role of monocyte chemoattractant protein-1 in experimental chronic pancreatitis model induced by Dibutyltin Dichloride in rats.
Pancreas, 2002Co-Authors: Masanobu Inoue, Yoshifumi Ino, Junya Gibo, Tetsuhide Ito, Terumasa Hisano, Yoshiyuki Arita, Hajime NawataAbstract:IntroductionRecently, Dibutyltin Dichloride (DBTC) was reported to induce pancreatic fibrosis within 28 days in rats, but it is not clear that the induced condition should be considered chronic pancreatitis.Aim and MethodologyThe aim of this study was to clarify whether the pancreatic fibrosis induc