title: Increased Expression of TGF-β Signaling Components in a Mouse Model of Fibrosis Induced by Submandibular Gland Duct Ligation.
abstract: Transforming growth factor-β (TGF-β) 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-β may contribute to salivary gland fibrosis, the expression of TGF-β 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-β1 and TGF-β3 were significantly upregulated in the SMG, as were TGF-β 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-β signaling components correlated with upregulation of fibrosis markers collagen 1 and fibronectin, responses that were inhibited by administration of the TGF-β receptor 1 inhibitors SB431542 or GW788388. After SMG regeneration following a 28 day duct deligation, TGF-β signaling components and epithelial-mesenchymal transition markers returned to levels similar to non-ligated controls. The results from this study indicate that increased TGF-β signaling contributes to duct ligation-induced changes in salivary epithelium that correlate with glandular fibrosis. Furthermore, the reversibility of enhanced TGF-β signaling in acinar cells of duct-ligated mouse SMG after deligation indicates that this is an ideal model for studying TGF-β signaling mechanisms in salivary epithelium as well as mechanisms of fibrosis initiation and their resolution.
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri, United States of America; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Lucas T
authors.initials: LT
authors.lastname: Woods
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri, United States of America; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Camden
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri, United States of America; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Farid G
authors.initials: FG
authors.lastname: El-Sayed
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri, United States of America; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Mahmoud G
authors.initials: MG
authors.lastname: Khalafalla
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri, United States of America; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, United States of America; Department of Nutritional Sciences and Exercise Physiology, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Petris
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri, United States of America; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Laurie
authors.initials: L
authors.lastname: Erb
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri, United States of America; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, United States of America.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Weisman
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D008026:Ligation; D008297:Male; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D013363:Submandibular Gland / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: C509927:4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide; D001549:Benzamides; D015415:Biomarkers; D015820:Cadherins; D020033:Protein Isoforms; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I