1. Inhibitors of Arg-Gly-Asp-Binding Integrins Reduce Development of Pancreatic Fibrosis in Mice
- Author
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Barbara Ulmasov, Jinping Lai, Vladimir Monastyrskiy, Matthew P. Yates, Brent A. Neuschwander-Tetri, Michael J. Prinsen, David W. Griggs, Peter G. Ruminski, Jonathan Oliva, and Trisha Bhat
- Subjects
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 - Abstract
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
- Published
- 2016
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