Increased Expression of TGF-[beta] Signaling Components in a Mouse Model of Fibrosis Induced by Submandibular Gland Duct Ligation

Transforming growth factor-[beta] (TGF-[beta]) is a multi-functional cytokine with a well-described role in the regulation of tissue fibrosis and regeneration in the liver, kidney and lung. Submandibular gland (SMG) duct ligation and subsequent deligation in rodents is a classical model for studying...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2015-05, Vol.10 (5)
Main Authors: Woods, Lucas T, Camden, Jean M, El-Sayed, Farid G, Khalafalla, Mahmoud G, Petris, Michael J, Erb, Laurie, Weisman, Gary A
Format: Article
Language:English
Subjects:
Bone morphogenetic proteins
Collagen
Cytokines
Fibronectins
Fibrosis
Stem cells
Transforming growth factors
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Transforming growth factor-[beta] (TGF-[beta]) is a multi-functional cytokine with a well-described role in the regulation of tissue fibrosis and regeneration in the liver, kidney and lung. Submandibular gland (SMG) duct ligation and subsequent deligation in rodents is a classical model for studying salivary gland damage and regeneration. While previous studies suggest that TGF-[beta] may contribute to salivary gland fibrosis, the expression of TGF-[beta] signaling components has not been investigated in relation to mouse SMG duct ligation-induced fibrosis and regeneration following ductal deligation. Following a 7 day SMG duct ligation, TGF-[beta]1 and TGF-[beta]3 were significantly upregulated in the SMG, as were TGF-[beta] receptor 1 and downstream Smad family transcription factors in salivary acinar cells, but not in ductal cells. In acinar cells, duct ligation also led to upregulation of snail, a Smad-activated E-cadherin repressor and regulator of epithelial-mesenchymal transition, whereas in ductal cells upregulation of E-cadherin was observed while snail expression was unchanged. Upregulation of these TGF-[beta] signaling components correlated with upregulation of fibrosis markers collagen 1 and fibronectin, responses that were inhibited by administration of the TGF-[beta] receptor 1 inhibitors SB431542 or GW788388. After SMG regeneration following a 28 day duct deligation, TGF-[beta] signaling components and epithelial-mesenchymal transition markers returned to levels similar to non-ligated controls. The results from this study indicate that increased TGF-[beta] signaling contributes to duct ligation-induced changes in salivary epithelium that correlate with glandular fibrosis. Furthermore, the reversibility of enhanced TGF-[beta] signaling in acinar cells of duct-ligated mouse SMG after deligation indicates that this is an ideal model for studying TGF-[beta] signaling mechanisms in salivary epithelium as well as mechanisms of fibrosis initiation and their resolution.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0123641