Connective Tissue Growth Factor in Pancreatitis

Connective Tissue Growth Factor in Pancreatitis

Bibliographic Details
Main Author: Charrier, Alyssa
Language:English
Published: The Ohio State University / OhioLINK 2013
Subjects:
Biology
Molecular Biology
connective tissue growth factor
fibrosis
pancreas
microRNA-21
inflammation
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1366025057
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1366025057
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Biology
Molecular Biology
connective tissue growth factor
fibrosis
pancreas
microRNA-21
inflammation
spellingShingle Biology
Molecular Biology
connective tissue growth factor
fibrosis
pancreas
microRNA-21
inflammation
Charrier, Alyssa
Connective Tissue Growth Factor in Pancreatitis
author Charrier, Alyssa
author_facet Charrier, Alyssa
author_sort Charrier, Alyssa
title Connective Tissue Growth Factor in Pancreatitis
title_short Connective Tissue Growth Factor in Pancreatitis
title_full Connective Tissue Growth Factor in Pancreatitis
title_fullStr Connective Tissue Growth Factor in Pancreatitis
title_full_unstemmed Connective Tissue Growth Factor in Pancreatitis
title_sort connective tissue growth factor in pancreatitis
publisher The Ohio State University / OhioLINK
publishDate 2013
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1366025057
work_keys_str_mv AT charrieralyssa connectivetissuegrowthfactorinpancreatitis
_version_ 1719419146059382784
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu13660250572021-08-03T05:22:06Z Connective Tissue Growth Factor in Pancreatitis Charrier, Alyssa Biology Molecular Biology connective tissue growth factor fibrosis pancreas microRNA-21 inflammation Pancreatitis is an inflammatory condition of the pancreas in which pancreatic acinar cells (PAC) become injured by noxious agents and produce pro-inflammatory mediators. Excessive alcohol consumption is a major cause of pancreatitis in the West. Acute pancreatitis (AP) can be recurrent and severe, leading to systemic inflammatory response syndrome, multiple organ dysfunction syndrome and death. Chronic pancreatitis (CP) involves tissue destruction, exocrine and endocrine insufficiency, increased risk of pancreatic cancer and an extensive fibrotic pathology which is due to unrelenting collagen deposition by pancreatic stellate cells (PSC). Improved understanding of the processes of inflammation and fibrosis are needed to identify the underlying mechanisms involved and to develop effective therapies, which are currently lacking. These studies reveal an important role for connective tissue growth factor (CTGF/CCN2) in pancreatic inflammation and fibrosis in a new model of experimental pancreatitis. Progress in studying alcohol pancreatitis has been hampered by the lack of a cost-effective, reproducible and efficient model in mice, reflecting their unusually high tolerance to ethanol. This difficulty was overcome by developing a model of episodic cerulein-induced AP which sensitized the pancreas to a "second-hit"; involving daily i.p. ethanol administration. By Day 23, these mice exhibited increased collagen deposition and an increased frequency of alpha-smooth muscle actin (α-SMA)- and desmin-positive PSC, which also showed significantly enhanced CTGF/CCN2 production. Expression of mRNA for collagen 1a(I), α-SMA or CTGF/CCN2 were all increased and co-localized exclusively to activated PSC. Pancreatic expression of mRNA for key profibrotic markers were all increased. These results show the successful development of a mouse model of alcoholic CP that mimics key pathophysiological features of the disease in humans and which shows that activated PSC are the principal producers of collagen and CTGF/CCN2.Production of CTGF/CCN2 by activated PSC was associated with enhanced expression of microRNA-21 (miR-21). A positive feedback loop between CTGF/CCN2 and miR-21 was identified that resulted in an enhancement of their respective expression as well as that of collagen 1a(I). Both miR-21 and CTGF/CCN2 mRNA were detected in nano-sized exosomes produced by PSC. Data supporting the uptake and expression of exosomal CTGF/CCN2 transcripts by either PSC or PAC were obtained, suggesting that PSC-derived CTGF/CCN2 mRNA is involved in epigenetic regulation of gene expression in these cells.CTGF/CCN2 was unexpectedly found to be produced by PAC in response to alcohol and this was a component of the inflammatory response in PAC before its role in PSC-mediated fibrogenesis. CTGF/CCN2 expression was up-regulated in PAC by ethanol or ethanol metabolites and it regulated production of the inflammatory mediators, interleukin-1β or chemokine (CC-motif) ligand 3. Expression of CTGF/CCN2 was associated with enhanced neutrophil or macrophage chemotaxis, the latter involving enhanced CCR-1 mediated signaling.In conclusion, CTGF/CCN2 is (i) involved in pathways of PSC fibrogenesis and PAC inflammation; (ii) exported from PSC in exosomes, which also contain miR-21; and (iii) a component of a positive feedback loop with miR-21 in PSC. These studies highlight CTGF/CCN2 and the CTGF/CCN2-miR-21 axis as potential targets in the effort to develop effective therapies for pancreatitis. 2013-08-09 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1366025057 http://rave.ohiolink.edu/etdc/view?acc_num=osu1366025057 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.

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