Rho/Rock cross‑talks with transforming growth factor‑β/Smad pathway participates in lung fibroblast‑myofibroblast differentiation

Ji,Hong; Tang,Haiying; Lin,Hongli; Mao,Jingwei; Gao,Lili; Liu,Jia; Wu,Taihua

doi:10.3892/br.2014.323

November-December 2014 Volume 2 Issue 6

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

November-December 2014 Volume 2 Issue 6

Full Size Image

Article Open Access

Rho/Rock cross‑talks with transforming growth factor‑β/Smad pathway participates in lung fibroblast‑myofibroblast differentiation

Authors:
- Hong Ji
- Haiying Tang
- Hongli Lin
- Jingwei Mao
- Lili Gao
- Jia Liu
- Taihua Wu
View Affiliations / Copyright

Affiliations: Department of Paediatrics, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Respiratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
Pages: 787-792
|
Published online on: July 31, 2014

https://doi.org/10.3892/br.2014.323
Expand metrics +

Abstract

The differentiation of fibroblasts, which are promoted by transforming growth factor‑β (TGF‑β)/Smad, is involved in the process of pulmonary fibrosis. The Rho/Rho‑associated coiled‑coil‑forming protein kinase (Rock) pathway may regulate the fibroblast differentiation and myofibroblast expression of α‑smooth muscle actin (α‑SMA), however, the mechanism is not clear. The aim of the present study was to evaluate the role of Rho/Rock and TGF‑β/Smad in TGF‑β1‑induced lung fibroblasts differentiation. Human embryonic lung fibroblasts were stimulated by TGF‑β1, Y‑27632 (inhibitor of Rho/Rock signaling) and staurosporine (inhibitor of TGF‑β/Smad signaling). The α‑SMA expression, cell cycle progression, content of the extracellular matrix (ECM) in cell culture supernatants and the expression of RhoA, RhoC, Rock1 and Smad2 were detected. The results demonstrated that α‑SMA‑positive cells significantly increased following TGF‑β1 stimulation. Rho/Rock and TGF‑β/Smad inhibitors suppressed TGF‑β1‑induced lung fibroblast differentiation. The inhibitors increased G0/G1 and decreased S and G2/M percentages. The concentrations of the ECM proteins in the supernatant were significantly increased by TGF‑β1 stimulation, whereas they were decreased by inhibitor stimulation. RhoA, RhoC, Rock1, Smad2 and tissue inhibitor of metalloproteinase‑1 were upregulated by TGF‑β1 stimulation. The Rho/Rock inhibitor downregulated Smad2 expression and the TGF‑β/Smad inhibitor downregulated RhoA, RhoC and Rock1 expression. Therefore, the Rho/Rock pathway and Smad signaling were involved in the process of lung fibroblasts transformation, induced by TGF‑β1, to myofibroblasts. The two pathways may undergo cross‑talk in the lung fibroblasts differentiation in vitro.

View Figures

View References

1	Warburton D, Shi W and Xu B: TGF-β-Smad3 signaling in emphysema and pulmonary fibrosis: an epigenetic aberration of normal development? Am J Physiol Lung Cell Mol Physiol. 304:L83–L85. 2012.
2	Antoniou KM, Margaritopoulos GA and Siafakas NM: Pharmacological treatment of idiopathic pulmonary fibrosis: from the past to the future. Eur Respir Rev. 22:281–291. 2013. View Article : Google Scholar : PubMed/NCBI
3	Harris WT, Kelly DR, Zhou Y, et al: Myfibroblast differentiation and enhanced TGF-β signaling in cystic fibrosis lung disease. PLoS One. 8:e701962013.
4	Moriyama T and Nagatoya K: The Rho-ROCK system as a new therapeutic target for preventing interstitial fibrosis. Drug News Perspect. 17:29–34. 2004. View Article : Google Scholar : PubMed/NCBI
5	Gao HC, Zhao H, Zhang WQ, Li YQ and Ren LQ: The role of the Rho/Rock signaling pathway in the pathogenesis of acute ischemic myocardial fibrosis in rat models. Exp Ther Med. 5:1123–1128. 2013.PubMed/NCBI
6	Liu M, Gu M, Wu Y, et al: Therapeutic effect of Y-27632 on chronic allograft nephropathy in rats. J Surg Res. 157:e117–e127. 2009. View Article : Google Scholar : PubMed/NCBI
7	Hu YB, Li X, Liang GN, Deng ZH, Jiang HY and Zhou JH: Roles of Rho/Rock signaling pathway in silica-induced epithelial-mesenchymal transition in human bronchial epithelial cells. Biomed Environ Sci. 26:571–576. 2013.PubMed/NCBI
8	Tada S, Iwamoto H, Nakamuta M, et al: A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats. J Hepatol. 34:529–536. 2001. View Article : Google Scholar : PubMed/NCBI
9	Kosanovic D, Dahal BK, Wygrecka M, et al: Mast cell chymase: an indispensable instrument in the pathological symphony of idiopathic pulmonary fibrosis? Histol Histopathol. 28:691–699. 2013.PubMed/NCBI
10	Günther A, Korfei M, Mahavadi P, von der Beck D, Ruppert C and Markart P: Unravelling the progressive pathophysiology of idiopathic pulmonary fibrosis. Eur Respir Rev. 21:152–160. 2012.PubMed/NCBI
11	Coward WR, Saini G and Jenkins G: The pathogenesis of idiopathic pulmonary fibrosis. Ther Adv Respir Dis. 4:367–388. 2010. View Article : Google Scholar : PubMed/NCBI
12	Wynn TA: Integrating mechanisms of pulmonary fibrosis. J Exp Med. 208:1339–1350. 2011. View Article : Google Scholar : PubMed/NCBI
13	Shimizu Y, Dobashi K, Iizuka K, et al: Contribution of small GTPase Rho and its target protein rock in a murine model of lung fibrosis. Am J Respir Crit Care Med. 163:210–217. 2001. View Article : Google Scholar : PubMed/NCBI
14	Nagatoya K, Moriyama T, Kawada N, et al: Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int. 61:1684–1695. 2002. View Article : Google Scholar : PubMed/NCBI
15	Murata T, Arii S, Mori A and Imamura M: Therapeutic significance of Y-27632, a Rho-kinase inhibitor, on the established liver fibrosis. J Surg Res. 114:64–71. 2003. View Article : Google Scholar : PubMed/NCBI
16	Mack CP, Somlyo AV, Hautmann M, Somlyo AP and Owens GK: Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization. J Biol Chem. 276:341–347. 2001. View Article : Google Scholar : PubMed/NCBI
17	Zhu J, Nguyen D, Ouyang H, Zhang XH, Chen XM and Zhang K: Inhibition of RhoA/Rho-kinase pathway suppresses the expression of extracellular matrix induced by CTGF or TGF-β in ARPE-19. Int J Ophthalmol. 6:8–14. 2013.
18	Zhou G, Li C and Cai L: Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor beta-independent pathway. Am J Pathol. 165:2033–2043. 2004. View Article : Google Scholar
19	Chen S, Crawford M, Day RM, et al: RhoA modulates Smad signaling during transforming growth factor-beta-induced smooth muscle differentiation. J Biol Chem. 281:1765–1770. 2006. View Article : Google Scholar : PubMed/NCBI
20	Itoh Y, Kimoto K, Imaizumi M and Nakatsuka K: Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGF-beta2 in human retinal pigment epithelial cells. Exp Eye Res. 84:464–472. 2007. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Rho/Rock cross‑talks with transforming growth factor‑β/Smad pathway participates in lung fibroblast‑myofibroblast differentiation

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Related Articles