Inhibitors of Arg-Gly-Asp-Binding Integrins Reduce Development of Pancreatic Fibrosis in Mice

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• 作者：Barbara Ulmasov¹ ; ^{bulmasov@slu.edu" class="auth_mail" title="E-mail the corresponding author} ; Brent A. Neuschwander-Tetri¹ ; Jinping Lai² ; Vladimir Monastyrskiy¹ ; Trisha Bhat¹ ; Matthew P. Yates³ ; Jonathan Oliva³ ; Michael J. Prinsen³ ; Peter G. Ruminski³ ; David W. Griggs³
• 关键词：Signal Transduction ; Pancreas ; Inflammation ; Peptidomimetic
• 刊名：CMGH Cellular and Molecular Gastroenterology and Hepatology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：2
• 期：4
• 页码：499-518
• 全文大小：5873 K

文摘

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.