A New Antifibrotic Target of Ac-SDKP: Inhibition of Myofibroblast Differentiation in Rat Lung with Silicosis

Hdl Handle:
http://hdl.handle.net/10675.2/804
Title:
A New Antifibrotic Target of Ac-SDKP: Inhibition of Myofibroblast Differentiation in Rat Lung with Silicosis
Authors:
Xu, Hong; Yang, Fang; Sun, Ying; Yuan, Yuan; Cheng, Hua; Wei, Zhongqiu; Li, Shuyu; Cheng, Tan; Brann, Darrell W ( 0000-0002-4480-8859 ) ; Wang, Ruimin
Abstract:
Background: Myofibroblast differentiation, characterized by a-smooth muscle actin (a-SMA) expression, is a key process in organ fibrosis, and is induced by TGF-b. Here we examined whether an anti-fibrotic agent, N-acetyl-seryl-aspartyllysylproline (Ac-SDKP), can regulate induction of TGF-b signaling and myofibroblast differentiation as a potential key component of its anti-fibrotic mechanism in vivo and in vitro.; Methodology/Principal Findings: Rat pulmonary fibroblasts were cultured in vitro and divided to 4 groups 1) control; 2) TGF-b1; 3) TGF-b1+ LY364947; 4) TGF-b1+Ac-SDKP. For in vivo studies, six groups of animals were utilized 1) control 4w; 2) silicotic 4w; 3) control 8w; 4) silicotic 8w; 5) Ac-SDKP post-treatment; 6)Ac-SDKP pre-treatment. SiO2 powders were douched in the trachea of rat to make the silicotic model. Myofibroblast differentiation was measured by examining expression of a- SMA, as well as expression of serum response factor (SRF), a key regulator of myofibroblast differentiation. The expressions of collagen, TGF-b1 and RAS signaling were also assessed. The results revealed that TGF-b1 strongly induced myofibroblast differentiation and collagen synthesis in vitro, and that pre-treatment with Ac-SDKP markedly attenuated myofibroblast activation, as well as induction of TGF-b1 and its receptor. Similar results were observed in vivo in the pathologically relevant rat model of silicosis. Ac-SDKP treatment in vivo strongly attenuated 1) silicosis-induced increased expressions of TGF-b1 and RAS signaling, 2) myofibroblast differentiation as indicated by a robust decrease of SRF and a-SMA-positive myofibroblast localization in siliconic nodules in the lung, 3) collagen deposition.; Conclusion/Significance: The results of the present study suggest a novel mechanism of action for Ac-SDKP’s beneficial effect in silicosis, which involves attenuation of TGF-b1 and its receptors, SRF and Ang II type 1 receptor (AT1) expression, collagen deposition and myofibroblast differentiation. The results further suggest that therapies targeting myofibroblast differentiation may have therapeutic efficacy in treatment of silicosis of the lung.
Citation:
PLoS One. 2012 Jul 3; 7(7):e40301
Issue Date:
3-Jul-2012
URI:
http://hdl.handle.net/10675.2/804
DOI:
10.1371/journal.pone.0040301
PubMed ID:
22802960
PubMed Central ID:
PMC3389005
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Institute of Molecular Medicine and Genetics: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorXu, Hongen_US
dc.contributor.authorYang, Fangen_US
dc.contributor.authorSun, Yingen_US
dc.contributor.authorYuan, Yuanen_US
dc.contributor.authorCheng, Huaen_US
dc.contributor.authorWei, Zhongqiuen_US
dc.contributor.authorLi, Shuyuen_US
dc.contributor.authorCheng, Tanen_US
dc.contributor.authorBrann, Darrell Wen_US
dc.contributor.authorWang, Ruiminen_US
dc.date.accessioned2012-10-26T20:30:47Z-
dc.date.available2012-10-26T20:30:47Z-
dc.date.issued2012-07-3en_US
dc.identifier.citationPLoS One. 2012 Jul 3; 7(7):e40301en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22802960en_US
dc.identifier.doi10.1371/journal.pone.0040301en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/804-
dc.description.abstractBackground: Myofibroblast differentiation, characterized by a-smooth muscle actin (a-SMA) expression, is a key process in organ fibrosis, and is induced by TGF-b. Here we examined whether an anti-fibrotic agent, N-acetyl-seryl-aspartyllysylproline (Ac-SDKP), can regulate induction of TGF-b signaling and myofibroblast differentiation as a potential key component of its anti-fibrotic mechanism in vivo and in vitro.en_US
dc.description.abstractMethodology/Principal Findings: Rat pulmonary fibroblasts were cultured in vitro and divided to 4 groups 1) control; 2) TGF-b1; 3) TGF-b1+ LY364947; 4) TGF-b1+Ac-SDKP. For in vivo studies, six groups of animals were utilized 1) control 4w; 2) silicotic 4w; 3) control 8w; 4) silicotic 8w; 5) Ac-SDKP post-treatment; 6)Ac-SDKP pre-treatment. SiO2 powders were douched in the trachea of rat to make the silicotic model. Myofibroblast differentiation was measured by examining expression of a- SMA, as well as expression of serum response factor (SRF), a key regulator of myofibroblast differentiation. The expressions of collagen, TGF-b1 and RAS signaling were also assessed. The results revealed that TGF-b1 strongly induced myofibroblast differentiation and collagen synthesis in vitro, and that pre-treatment with Ac-SDKP markedly attenuated myofibroblast activation, as well as induction of TGF-b1 and its receptor. Similar results were observed in vivo in the pathologically relevant rat model of silicosis. Ac-SDKP treatment in vivo strongly attenuated 1) silicosis-induced increased expressions of TGF-b1 and RAS signaling, 2) myofibroblast differentiation as indicated by a robust decrease of SRF and a-SMA-positive myofibroblast localization in siliconic nodules in the lung, 3) collagen deposition.en_US
dc.description.abstractConclusion/Significance: The results of the present study suggest a novel mechanism of action for Ac-SDKP’s beneficial effect in silicosis, which involves attenuation of TGF-b1 and its receptors, SRF and Ang II type 1 receptor (AT1) expression, collagen deposition and myofibroblast differentiation. The results further suggest that therapies targeting myofibroblast differentiation may have therapeutic efficacy in treatment of silicosis of the lung.en_US
dc.rightsXu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectImmune Physiologyen_US
dc.subjectCytokinesen_US
dc.subjectImmunologyen_US
dc.subjectImmune Systemen_US
dc.subjectCytokinesen_US
dc.subjectImmunityen_US
dc.subjectInflammationen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectSignal Transductionen_US
dc.subjectSignaling Cascadesen_US
dc.subjectTGF-beta signaling cascadeen_US
dc.subjectMedicineen_US
dc.subjectClinical Immunologyen_US
dc.subjectImmunityen_US
dc.subjectInflammationen_US
dc.subjectPulmonologyen_US
dc.subjectEnvironmental and Occupational Lung Diseasesen_US
dc.subjectPneumoconiosesen_US
dc.titleA New Antifibrotic Target of Ac-SDKP: Inhibition of Myofibroblast Differentiation in Rat Lung with Silicosisen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3389005en_US
dc.contributor.corporatenameInstitute of Molecular Medicine and Genetics-

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