Maresin 1 inhibits transforming growth factor-β1-induced proliferation, migration and differentiation in human lung fibroblasts

Sun,Quanchao; Wu,You; Zhao,Feng; Wang,Jianjun

doi:10.3892/mmr.2017.6711

Maresin 1 inhibits transforming growth factor-β1-induced proliferation, migration and differentiation in human lung fibroblasts

Authors:
- Quanchao Sun
- You Wu
- Feng Zhao
- Jianjun Wang
View Affiliations

Affiliations: Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: June 7, 2017 https://doi.org/10.3892/mmr.2017.6711
Pages: 1523-1529
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The myofibroblast has been implicated to be an important pathogenic cell in all fibrotic diseases, through synthesis of excess extracellular matrix. Lung fibroblast migration, proliferation and differentiation into a myofibroblast‑like cell type are regarded as important steps in the formation of lung fibrosis. In the present study, the effect of maresin 1 (MaR 1), a pro‑resolving lipid mediator, on transforming growth factor (TGF)‑β1‑stimulated lung fibroblasts was investigated, and the underlying molecular mechanisms were examined. The results of the present study demonstrated that MaR 1 inhibited TGF‑β1‑induced proliferative and migratory ability, assessed using MTT and scratch wound healing assays. The TGF‑β1‑induced expression of α‑smooth muscle actin (α‑SMA) and collagen type I, the hallmarks of myofibroblast differentiation, was decreased by MaR 1 at the mRNA and protein levels, determined using the reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. Immunofluorescence demonstrated that MaR 1 downregulated the TGF‑β1‑induced expression of α‑SMA. In addition, phosphorylated mothers against decapentaplegic homolog 2/3 (Smad2/3) and extracellular signal‑related kinases (ERK) 1/2 were upregulated in TGF-β1-induced lung fibroblasts, and these effects were attenuated by MaR 1 administration. In conclusion, the results of the present study demonstrated that MaR 1 inhibited the TGF‑β1‑induced proliferation, migration and differentiation of human lung fibroblasts. These observed effects may be mediated in part by decreased phosphorylation of Smad2/3 and ERK1/2 signaling pathways. Therefore, MaR 1 may be a potential therapeutic approach to lung fibrotic diseases.

View Figures

View References

1	Postma DS and Timens W: Remodeling in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc. 3:434–439. 2006. View Article : Google Scholar : PubMed/NCBI
2	Ding NH, Li JJ and Sun LQ: Molecular mechanisms and treatment of radiation-induced lung fibrosis. Curr Drug Targets. 14:1347–1356. 2013. View Article : Google Scholar : PubMed/NCBI
3	Ramirez AM, Shen Z, Ritzenthaler JD and Roman J: Myofibroblast transdifferentiation in obliterative bronchiolitis: Tgf-beta signaling through smad3-dependent and -independent pathways. Am J Transplant. 6:2080–2088. 2006. View Article : Google Scholar : PubMed/NCBI
4	Wilson MS and Wynn TA: Pulmonary fibrosis: Pathogenesis, etiology and regulation. Mucosal Immunol. 2:103–121. 2009. View Article : Google Scholar : PubMed/NCBI
5	Noble PW, Barkauskas CE and Jiang D: Pulmonary fibrosis: Patterns and perpetrators. J Clin Invest. 122:2756–2762. 2012. View Article : Google Scholar : PubMed/NCBI
6	Maharaj S, Shimbori C and Kolb M: Fibrocytes in pulmonary fibrosis: A brief synopsis. Eur Respir Rev. 22:552–557. 2013. View Article : Google Scholar : PubMed/NCBI
7	Sivakumar P, Ntolios P, Jenkins G and Laurent G: Into the matrix: Targeting fibroblasts in pulmonary fibrosis. Curr Opin Pulm Med. 18:462–469. 2012. View Article : Google Scholar : PubMed/NCBI
8	Phan SH: The myofibroblast in pulmonary fibrosis. Chest. 122 Suppl 6:S286–S289. 2002. View Article : Google Scholar
9	Serhan CN: Pro-resolving lipid mediators are leads for resolution physiology. Nature. 510:92–101. 2014. View Article : Google Scholar : PubMed/NCBI
10	Serhan CN and Chiang N: Resolution phase lipid mediators of inflammation: Agonists of resolution. Curr Opin Pharmacol. 13:632–640. 2013. View Article : Google Scholar : PubMed/NCBI
11	Dalli J, Zhu M, Vlasenko NA, Deng B, Haeggström JZ, Petasis NA and Serhan CN: The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB J. 27:2573–2583. 2013. View Article : Google Scholar : PubMed/NCBI
12	Marcon R, Bento AF, Dutra RC, Bicca MA, Leite DF and Calixto JB: Maresin 1, a proresolving lipid mediator derived from omega-3 polyunsaturated fatty acids, exerts protective actions in murine models of colitis. J Immunol. 191:4288–4298. 2013. View Article : Google Scholar : PubMed/NCBI
13	Nordgren TM, Heires AJ, Wyatt TA, Poole JA, LeVan TD, Cerutis DR and Romberger DJ: Maresin-1 reduces the pro-inflammatory response of bronchial epithelial cells to organic dust. Respir Res. 14:512013. View Article : Google Scholar : PubMed/NCBI
14	Gong J, Wu ZY, Qi H, Chen L, Li HB, Li B, Yao CY, Wang YX, Wu J, Yuan SY, et al: Maresin 1 mitigates LPS-induced acute lung injury in mice. Br J Pharmacol. 171:3539–3550. 2014. View Article : Google Scholar : PubMed/NCBI
15	Li R, Wang Y, Zhao E, Wu K, Li W, Shi L, Wang D, Xie G, Yin Y, Deng M, et al: Maresin 1, a proresolving lipid mediator, mitigates carbon tetrachloride-induced liver injury in mice. Oxid Med Cell Longev. 2016:92037162016.PubMed/NCBI
16	Akagi D, Chen M, Toy R, Chatterjee A and Conte MS: Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice. FASEB J. 29:2504–2513. 2015. View Article : Google Scholar : PubMed/NCBI
17	Wang Y, Li R, Chen L, Tan W, Sun Z, Xia H, Li B, Yu Y, Gong J, Tang M, et al: Maresin 1 inhibits epithelial-to-mesenchymal transition in vitro and attenuates bleomycin induced lung fibrosis in vivo. Shock. 44:496–502. 2015. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML and Gabbiani G: The myofibroblast: One function, multiple origins. Am J Pathol. 170:1807–1816. 2007. View Article : Google Scholar : PubMed/NCBI
20	Santana A, Saxena B, Noble NA, Gold LI and Marshall BC: Increased expression of transforming growth factor beta isoforms (beta 1, beta 2, beta 3) in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 13:34–44. 1995. View Article : Google Scholar : PubMed/NCBI
21	Yang S, Cui H, Xie N, Icyuz M, Banerjee S, Antony VB, Abraham E, Thannickal VJ and Liu G: miR-145 regulates myofibroblast differentiation and lung fibrosis. FASEB J. 27:2382–2391. 2013. View Article : Google Scholar : PubMed/NCBI
22	Wu SH, Wu XH, Lu C, Dong L and Chen ZQ: Lipoxin A4 inhibits proliferation of human lung fibroblasts induced by connective tissue growth factor. Am J Respir Cell Mol Biol. 34:65–72. 2006. View Article : Google Scholar : PubMed/NCBI
23	Wu SH, Wu XH, Lu C, Dong L, Zhou GP and Chen ZQ: Lipoxin A4 inhibits connective tissue growth factor-induced production of chemokines in rat mesangial cells. Kidney Int. 69:248–256. 2006. View Article : Google Scholar : PubMed/NCBI
24	Fierro IM, Kutok JL and Serhan CN: Novel lipid mediator regulators of endothelial cell proliferation and migration: Aspirin-triggered-15R-lipoxin A(4) and lipoxin A(4). J Pharmacol Exp Ther. 300:385–392. 2002. View Article : Google Scholar : PubMed/NCBI
25	Blobe GC, Schiemann WP and Lodish HF: Role of transforming growth factor beta in human disease. N Engl J Med. 342:1350–1358. 2000. View Article : Google Scholar : PubMed/NCBI
26	Camoretti-Mercado B and Solway J: Transforming growth factor-beta1 and disorders of the lung. Cell Biochem Biophys. 43:131–148. 2005. View Article : Google Scholar : PubMed/NCBI
27	Samarakoon R, Overstreet JM and Higgins PJ: TGF-β signaling in tissue fibrosis: Redox controls, target genes and therapeutic opportunities. Cell Signal. 25:264–268. 2013. View Article : Google Scholar : PubMed/NCBI
28	Dong Z, Zhao X, Tai W, Lei W, Wang Y, Li Z and Zhang T: IL-27 attenuates the TGF-β1-induced proliferation, differentiation and collagen synthesis in lung fibroblasts. Life Sci. 146:24–33. 2016. View Article : Google Scholar : PubMed/NCBI
29	Harris WT, Kelly DR, Zhou Y, Wang D, MacEwen M, Hagood JS, Clancy JP, Ambalavanan N and Sorscher EJ: Myofibroblast differentiation and enhanced TGF-B signaling in cystic fibrosis lung disease. PLoS One. 8:e701962013. View Article : Google Scholar : PubMed/NCBI
30	Tumelty KE, Smith BD, Nugent MA and Layne MD: Aortic carboxypeptidase-like protein (ACLP) enhances lung myofibroblast differentiation through transforming growth factor β receptor-dependent and -independent pathways. J Biol Chem. 289:2526–2536. 2014. View Article : Google Scholar : PubMed/NCBI
31	Lee CC, Wang CN, Lee YL, Tsai YR and Liu JJ: High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9. PLoS One. 10:e01163932015. View Article : Google Scholar : PubMed/NCBI
32	Park S, Ahn JY, Lim MJ, Kim MH, Lee SL, Yun YS, Jeong G and Song JY: IM-412 inhibits transforming growth factor beta-induced fibroblast differentiation in human lung fibroblast cells. Biochem Biophys Res Commun. 399:268–273. 2010. View Article : Google Scholar : PubMed/NCBI
33	Chung MJ, Liu T, Ullenbruch M and Phan SH: Antiapoptotic effect of found in inflammatory zone (FIZZ)1 on mouse lung fibroblasts. J Pathol. 212:180–187. 2007. View Article : Google Scholar : PubMed/NCBI
34	Hough C, Radu M and Doré JJ: Tgf-beta induced Erk phosphorylation of smad linker region regulates smad signaling. PLoS One. 7:e425132012. View Article : Google Scholar : PubMed/NCBI