Inhibitors of Arg-Gly-Asp-Binding Integrins Reduce Development of Pancreatic Fibrosis in Mice
| Autor: | Barbara Ulmasov, Jinping Lai, Vladimir Monastyrskiy, Matthew P. Yates, Brent A. Neuschwander-Tetri, Michael J. Prinsen, David W. Griggs, Peter G. Ruminski, Jonathan Oliva, Trisha Bhat |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
DMEM Dulbecco's modified Eagle medium Pancreatic stellate cell IC50 median inhibitory concentration DMSO dimethyl sulfoxide Cell morphology LAP latency-associated peptide PCR polymerase chain reaction Fibrosis LTC-14 large T immortalized cells MLEC mink lung epithelial cell Original Research biology CWHM Center for World Health and Medicine PSC pancreatic stellate cell Gastroenterology mPSC mouse pancreatic stellate cell mRNA messenger RNA ECM extracellular matrix medicine.anatomical_structure TGFB transforming growth factor β Pancreas Col1a1 collagen type I α1 Signal Transduction medicine.medical_specialty Peptidomimetic Integrin PBS phosphate-buffered saline CTGF connective tissue growth factor α-SMA α-smooth muscle actin 03 medical and health sciences FBS fetal bovine serum Internal medicine medicine Acinar cell p-SMAD phosphorylated SMAD CP chronic pancreatitis lcsh:RC799-869 Inflammation Hepatology medicine.disease CTGF 030104 developmental biology Endocrinology RGD arginine-glycine-aspartic acid biology.protein Cancer research Hepatic stellate cell lcsh:Diseases of the digestive system. Gastroenterology MMP matrix metallopeptidase |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 2, Iss 4, Pp 499-518 (2016) |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2016.03.004 |
| Popis: | Background & Aims: Pancreatic stellate cells (PSCs) regulate the development of chronic pancreatitis (CP) and are activated by the cytokine transforming growth factor β (TGFB). Integrins of the αv family promote TGFB signaling in mice, probably by interacting with the Arg-Gly-Asp (RGD) sequence of the TGFB latency-associated peptide, which frees TGFB to bind its cellular receptors. However, little is known about the role of integrins in the development of CP. We investigated the effects of small-molecule integrin inhibitors in a mouse model of CP. Methods: We induced CP in C57BL/6 female mice by repeated cerulein administration. An active RGD peptidomimetic compound (Center for World Health and Medicine [CWHM]-12) was delivered by continuous infusion, starting 3 days before or 5 days after cerulein administration began. Pancreata were collected and parenchymal atrophy, fibrosis, and activation of PSCs were assessed by histologic, gene, and protein expression analyses. We measured CWHM-12 effects on activation of TGFB in co-culture assays in which rat PSC cells (large T immortalized cells [LTC-14]) activate expression of a TGFB-sensitive promoter in reporter cells. Results: Pancreatic tissues of mice expressed messenger RNAs encoding subunits of RGD-binding integrins. Cerulein administration increased expression of these integrins, altered pancreatic cell morphology, and induced fibrosis. The integrin inhibitor CWHM-12 decreased acinar cell atrophy and loss, and substantially reduced fibrosis, activation of PSCs, and expression of genes regulated by TGFB. CWHM-12 also reduced established fibrosis in mice and blocked activation of TGFB in cultured cells. Conclusions: Based on studies of a mouse model of CP and cultured PSCs, integrins that bind RGD sequences activate PSCs and promote the development of pancreatic fibrogenesis in mice. Small-molecule antagonists of this interaction might be developed for treatment of pancreatic fibrotic diseases. Keywords: Signal Transduction, Pancreas, Inflammation, Peptidomimetic |
| Databáze: | OpenAIRE |
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