Identification of quantitative trait loci for murine autoimmune pancreatitis

Asghari, Farahnaz; Fitzner, Brit; Holzhüter, Stephanie-Anna; Nizze, H; Marques, António; Müller, Susen; Möller, Steffen; Ibrahim, Saleh M.; Jaster, Robert

doi:10.1136/jmg.2011.089730

Cited by 17 publications

(53 citation statements)

References 48 publications

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“…Another disease observed in NOD mice is inflammation of the pancreas 25 that is also observed in the MRL/Mp and MRL/Mp-Fas models of AIP 26, 27 . Accordingly, Figures 4a, b and S2b, show inflammatory foci and high level of collagen in the endocrine (islet in Figure 4a, top left image) and exocrine pancreas that is infiltrated by T and B cells and neutrophils.…”

Section: Resultsmentioning

confidence: 89%

Correction of Ductal CFTR Activity Rescues Acinar Cell and Pancreatic and Salivary Gland Functions in Mouse Models of Autoimmune Disease

et al. 2017

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BACKGROUND & AIMS Sjögren’s syndrome and autoimmune pancreatitis (AIP) are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. NOD/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjögren’s syndrome and chronic pancreatitis and MRL/Mp mice are models of AIP. CFTR is a ductal Cl− channel essential for ductal fluid and HCO3− secretion. We used these models to ask: is CFTR expression altered in these diseases, does correction of CFTR correct gland function, and most notably, does correcting ductal function correct acinar function. Methods We treated the mice models with the CFTR corrector C18 and the potentiator VX770. Glandular, ductal and acinar cells damage, infiltration of immune cells, and function were measured in vivo and in isolated duct/acini. Results In the disease models, CFTR expression is markedly reduced. The salivary glands and pancreas are inflamed with increased fibrosis and tissue damage. Treatment with VX770 and, in particular C18 restored salivation, rescued CFTR expression and localization, nearly eliminated the inflammation and tissue damage. Transgenic over-expression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca2+ signaling, Orai1, IP3 receptors, AQP5 expression and fluid secretion were restored by rescuing ductal CFTR. Conclusions Our findings reveal that correcting ductal function is sufficient to rescue acinar cell function and suggests that CFTR correctors are strong candidates for the treatment of Sjögren’s syndrome and pancreatitis.

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Section: Resultsmentioning

confidence: 89%

Correction of Ductal CFTR Activity Rescues Acinar Cell and Pancreatic and Salivary Gland Functions in Mouse Models of Autoimmune Disease

et al. 2017

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“…Fibrosis was further evaluated within distinct anatomic compartments: intralobular = fibrosis within lobules that separates, surrounds, and dissects exocrine acini; perilobular = circumferential fibrosis around lobules, interlobular = non-circumferential between lobules; and periductal = circumferential around ducts. The degree of inflammatory response was graded was according to previously published criteria, 34 and the scoring criteria for inflammation are shown in Table 2.…”

Section: Methodsmentioning

confidence: 99%

Cholecystokinin Receptor Antagonist Halts Progression of Pancreatic Cancer Precursor Lesions and Fibrosis in Mice

Smith¹,

Cooper²,

McGovern³

et al. 2014

Pancreas

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Objectives Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved with the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer. Methods The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-KrasG12D transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK-receptor antagonist (proglumide, 0.1mg/ml). Pancreas from mice were removed and examined histologically for number and grade of PanINs after 1, 2 or 4 months of antagonist therapy. Results Both CCK-A and CCK-B receptors were identified in early stage PanINs from mouse and human pancreas. The grade of PanIN lesions was reversed and progression to advanced lesions arrested in mice treated with proglumide compared to controls (p=0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared to vehicle (pitalic>0.001). Conclusions These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. Use of CCK-receptor antagonists may have a role in cancer prophylaxis in high risk subjects, and may reduce fibrosis in the microenvironment.

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“…Spleen, liver, lung and pancreas were harvested and analysed by flow cytometry, fixed and cryo- or paraffin-embedded and used for further immunhistochemistry 29 30 34 35…”

Section: Methodsmentioning

confidence: 99%

Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment

Schwaiger

Brandt

Fitzner

et al. 2013

Gut

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Identification of quantitative trait loci for murine autoimmune pancreatitis

Abstract: This study has identified QTLs and putative candidate genes of murine AIP. Their functional role and relevance to human AIP will be studied further.

Cited by 17 publications

References 48 publications

Correction of Ductal CFTR Activity Rescues Acinar Cell and Pancreatic and Salivary Gland Functions in Mouse Models of Autoimmune Disease

Correction of Ductal CFTR Activity Rescues Acinar Cell and Pancreatic and Salivary Gland Functions in Mouse Models of Autoimmune Disease

Cholecystokinin Receptor Antagonist Halts Progression of Pancreatic Cancer Precursor Lesions and Fibrosis in Mice

Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment

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