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

Autor:	Ulmasov B; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri., Neuschwander-Tetri BA; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri., Lai J; Department of Pathology, Saint Louis University, Saint Louis, Missouri., Monastyrskiy V; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri., Bhat T; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri., Yates MP; Center for World Health and Medicine, Saint Louis University, Saint Louis, Missouri., Oliva J; Center for World Health and Medicine, Saint Louis University, Saint Louis, Missouri., Prinsen MJ; Center for World Health and Medicine, Saint Louis University, Saint Louis, Missouri., Ruminski PG; Center for World Health and Medicine, Saint Louis University, Saint Louis, Missouri., Griggs DW; Center for World Health and Medicine, Saint Louis University, Saint Louis, Missouri.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2016 Mar 16; Vol. 2 (4), pp. 499-518. Date of Electronic Publication: 2016 Mar 16 (Print Publication: 2016).
DOI:	10.1016/j.jcmgh.2016.03.004
Abstrakt:	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.
Databáze:	MEDLINE
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