HAL will be down for maintenance from Friday, June 10 at 4pm through Monday, June 13 at 9am. More information
Skip to Main content Skip to Navigation
Journal articles

Glycosyltransferases and Glycosaminoglycans in Bleomycin and Transforming Growth Factor-beta 1-Induced Pulmonary Fibrosis

Abstract : Glycosaminoglycan (GAG) chains of proteoglycans (PGs) play important roles in fibrosis through cell-matrix interactions and growth factor binding in the extracellular matrix. We investigated the expression and regulation of PG core protein (versican) and key enzymes (xylosyltransferase [XT]-I, beta 1,3-glucuronosyltransferase [GlcAT]-I, chondroitin-4-sulfotransferase [C4ST]) implicated in synthesis and sulfation of GAGs in bleomycin (BLM) and adenovirus-transforming growth factor (TGF)-beta 1-induced lung fibrosis in rats. We also studied the role of GlcAT-I or TGF-beta 1 and the signaling pathways regulating PG-GAG production in primary lung fibroblasts isolated from saline-or BLM-instilled rats. The mRNA for XT-I, GlcAT-I, C4ST, and versican was increased in the lung 14 days after BLM injury. In vitro studies indicate that fibrotic lung fibroblasts (FLFs) expressed more XT-I, C4ST, and chondroitin sulfate (CS)-GAGs than did normal lung fibroblasts at baseline. TGF-beta 1 enhanced the expression of XT-I, C4ST-I, and versican in normal lung fibroblasts, whereas SB203580 or SB431542, by targeting p38 mitogen-activated protein kinase or TGF-b type-1 receptor/activin receptor-like kinase 5, respectively, attenuated the response to both TGF-beta 1 and FLFs on PG-GAG expression. Neutralizing anti-TGF-beta 1 antibody abrogated FLF-conditioned medium-stimulated expression of XT-I, GlcAT-I, versican, and CS-GAG. Forced expression of TGF-beta 1 in vivo enhanced versican, XT-I, GlcAT-I, and C4ST-I expression and PG-GAG deposition in rat lungs. Finally, induced expression of GlcAT-I gene in rat lung fibroblasts increased GAG synthesis by these cells. Together, our results provide new insights into the basis for increased PG-GAG deposition in lung fibrosis; inhibition of TGF-beta 1-mediated or fibrosis-induced PGGAG production by activin receptor-like kinase 5/p38 inhibitors may contribute to antifibrotic activity.
Complete list of metadata

https://hal.univ-lorraine.fr/hal-01452707
Contributor : Imopa Ul Connect in order to contact the contributor
Submitted on : Thursday, February 2, 2017 - 10:43:30 AM
Last modification on : Friday, February 4, 2022 - 3:56:35 PM

Identifiers

Citation

Narayanan Venkatesan, Kimitake Tsuchiya, Martin Kolb, Laszlo Farkas, Mustapha Bourhim, et al.. Glycosyltransferases and Glycosaminoglycans in Bleomycin and Transforming Growth Factor-beta 1-Induced Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology, American Thoracic Society, 2014, 50 (3), pp.583-594. ⟨10.1165/rcmb.2012-0226OC⟩. ⟨hal-01452707⟩

Share

Metrics

Record views

21