Generic placeholder image

Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

General Research Article

Ticagrelor Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats by the Inhibition of TGF-β1/Smad3 and PI3K/AKT/mTOR Pathways

Author(s): Hanaa Wanas*, Zeinab El Shereef, Laila Rashed and Basma Emad Aboulhoda

Volume 15, Issue 1, 2022

Published on: 04 February, 2021

Page: [227 - 238] Pages: 12

DOI: 10.2174/1874467214666210204212533


Background: Idiopathic pulmonary fibrosis (IPF) is a serious disease with a high mortality rate. Activation of transforming growth factor (TGF)-β1 production and signalling are considered the cornerstone in the epithelial-mesenchymal transition (EMT) process. EMT plays a central role in the development of fibrosis in many organs including the lungs. Activated platelets are an important source of TGF-β1 and play a pivotal role in EMT and fibrosis process. The antiplatelet, ticagrelor was previously found to inhibit the EMT in different types of cancer cells, but its ability to serve as an anti-pulmonary fibrosis (PF) agent was not previously investigated.

Objective: In this study, we aim to investigate the potential ability of ticagrelor to ameliorate bleomycin-induced fibrosis in rats.

Methods: PF was induced in rats by intratracheal BLM at a dose of 3 mg/kg. The effect of daily 20 mg/kg oral ticagrelor on different histological and biochemical parameters of fibrosis was investigated

Results: Our results revealed that ticagrelor can alleviate lung fibrosis. We found that ticagrelor inhibited TGF-β1 production and suppressed Smad3 activation and signaling pathway with subsequent inhibition of Slug and Snail. In addition, ticagrelor antagonized PI3K/AKT/mTOR pathway signaling. Moreover, ticagrelor inhibited the EMT that was revealed by its ability to up-regulate the epithelial markers as E-cadherin (E-cad) and to decrease the expression of the mesenchymal markers as vimentin (VIM) and alpha-smooth muscle actin (α-SMA).

Conclusion: Our results suggest that the P2Y12 inhibitor, ticagrelor may have a therapeutic potential in reducing the progression of PF.

Keywords: Lung fibrosis, ticagrelor, bleomycin, TGF-β1, epithelial-mesenchymal transition, platelets.

Graphical Abstract
Aravena, C.; Labarca, G.; Venegas, C.; Arenas, A.; Rada, G. Pirfenidone for Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.PLoS One, 2015, 10(8), e0136160.
Wynn, T.A. Integrating mechanisms of pulmonary fibrosis. J. Exp. Med., 2011, 208(7), 1339-1350.
[] [PMID: 21727191]
Eferl, R.; Hasselblatt, P.; Rath, M.; Popper, H.; Zenz, R.; Komnenovic, V.; Idarraga, M.H.; Kenner, L.; Wagner, E.F. Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Proc. Natl. Acad. Sci. USA, 2008, 105(30), 10525-10530.
[] [PMID: 18641127]
Manetti, M.; Rosa, I.; Milia, A.F.; Guiducci, S.; Carmeliet, P.; Ibba-Manneschi, L.; Matucci-Cerinic, M. Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma? Ann. Rheum. Dis., 2014, 73(9), 1700-1709.
[] [PMID: 23852693]
Willis, B.C.; Liebler, J.M.; Luby-Phelps, K.; Nicholson, A.G.; Crandall, E.D.; du Bois, R.M.; Borok, Z. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: potential role in idiopathic pulmonary fibrosis. Am. J. Pathol., 2005, 166(5), 1321-1332.
[] [PMID: 15855634]
Alder, J.K.; Chen, J.J-L.; Lancaster, L.; Danoff, S.; Su, S.C.; Cogan, J.D.; Vulto, I.; Xie, M.; Qi, X.; Tuder, R.M.; Phillips, J.A., III; Lansdorp, P.M.; Loyd, J.E.; Armanios, M.Y. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl. Acad. Sci. USA, 2008, 105(35), 13051-13056.
[] [PMID: 18753630]
Alder, J.K.; Kass, D.J. Another building in the IPF Manhattan plot skyline. Lancet Respir. Med., 2017, 5(11), 837-839.
[] [PMID: 29066087]
Fehrenbach, H. Alveolar epithelial type II cell: defender of the alveolus revisited. Respir. Res., 2001, 2(1), 33-46.
[] [PMID: 11686863]
Taskar, V.S.; Coultas, D.B. Is idiopathic pulmonary fibrosis an environmental disease? Proc. Am. Thorac. Soc., 2006, 3(4), 293-298.
[] [PMID: 16738192]
Zoz, D.F.; Lawson, W.E.; Blackwell, T.S. Idiopathic pulmonary fibrosis: a disorder of epithelial cell dysfunction. Am. J. Med. Sci., 2011, 341(6), 435-438.
[] [PMID: 21613930]
Câmara, J.; Jarai, G. Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-α. Fibrogenesis Tissue Repair, 2010, 3(1), 2.
[] [PMID: 20051102]
Moustakas, A.; Heldin, C.H. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci., 2007, 98(10), 1512-1520.
[PMID: 17645776]
Guan, R.; Wang, X.; Zhao, X.; Song, N.; Zhu, J.; Wang, J.; Wang, J.; Xia, C.; Chen, Y.; Zhu, D.; Shen, L. Emodin ameliorates bleomycin-induced pulmonary fibrosis in rats by suppressing epithelial-mesenchymal transition and fibroblast activation. Sci. Rep., 2016, 6(1), 35696.
[] [PMID: 27774992]
Lamouille, S.; Derynck, R. Cell size and invasion in TGF-β-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J. Cell Biol., 2007, 178(3), 437-451.
[] [PMID: 17646396]
Labelle, M.; Begum, S.; Hynes, R.O. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell, 2011, 20(5), 576-590.
[] [PMID: 22094253]
Cho, M.S.; Bottsford-Miller, J.; Vasquez, H.G.; Stone, R.; Zand, B.; Kroll, M.H.; Sood, A.K.; Afshar-Kharghan, V. Platelets increase the proliferation of ovarian cancer cells. Blood, 2012, 120(24), 4869-4872.
[] [PMID: 22966171]
Guillem-Llobat, P.; Dovizio, M.; Bruno, A.; Ricciotti, E.; Cufino, V.; Sacco, A.; Grande, R.; Alberti, S.; Arena, V.; Cirillo, M.; Patrono, C.; FitzGerald, G.A.; Steinhilber, D.; Sgambato, A.; Patrignani, P. Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget, 2016, 7(22), 32462-32477.
[] [PMID: 27074574]
Dovizio, M.; Maier, T.J.; Alberti, S.; Di Francesco, L.; Marcantoni, E.; Münch, G.; John, C.M.; Suess, B.; Sgambato, A.; Steinhilber, D.; Patrignani, P. Pharmacological inhibition of platelet-tumor cell cross-talk prevents platelet-induced overexpression of cyclooxygenase-2 in HT29 human colon carcinoma cells. Mol. Pharmacol., 2013, 84(1), 25-40.
[] [PMID: 23580446]
Cho, M.S.; Noh, K.; Haemmerle, M.; Li, D.; Park, H.; Hu, Q.; Hisamatsu, T.; Mitamura, T.; Mak, S.L.C.; Kunapuli, S.; Ma, Q.; Sood, A.K.; Afshar-Kharghan, V. Role of ADP receptors on platelets in the growth of ovarian cancer. Blood, 2017, 130(10), 1235-1242.
[] [PMID: 28679740]
Dovizio, M.; Bruno, A.; Contursi, A.; Grande, R.; Patrignani, P. Platelets and extracellular vesicles in cancer: diagnostic and therapeutic implications. Cancer Metastasis Rev., 2018, 37(2-3), 455-467.
[] [PMID: 29855749]
Mezouar, S.; Darbousset, R.; Dignat-George, F.; Panicot-Dubois, L.; Dubois, C. Inhibition of platelet activation prevents the P-selectin and integrin-dependent accumulation of cancer cell microparticles and reduces tumor growth and metastasis in vivo. Int. J. Cancer, 2015, 136(2), 462-475.
[PMID: 24889539]
Gao, L.; Tang, H.; He, H.; Liu, J.; Mao, J.; Ji, H.; Lin, H.; Wu, T. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats. Front. Pharmacol., 2015, 6(OCT), 215.
[PMID: 26483688]
Ashcroft, T.; Simpson, J.M.; Timbrell, V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J. Clin. Pathol., 1988, 41(4), 467-470.
[] [PMID: 3366935]
Aboulhoda, B.E.; Abd El Fattah, S. Bone marrow-derived versus adipose-derived stem cells in wound healing: value and route of administration. Cell Tissue Res., 2018, 374(2), 285-302.
[] [PMID: 29987390]
Wang, B-L.; Tu, Y-Y.; Fu, J-F.; Zhong, Y-X.; Fu, G.Q.; Tian, X-X.; Wang, L.H.; Gong, L.; Ren, Q.Y. Unbalanced MMP/TIMP-1 expression during the development of experimental pulmonary fibrosis with acute paraquat poisoning. Mol. Med. Rep., 2011, 4(2), 243-248.
[] [PMID: 21468558]
Afratis, N.A.; Selman, M.; Pardo, A.; Sagi, I. Emerging insights into the role of matrix metalloproteases as therapeutic targets in fibrosis. Matrix Biol., 2018, 68-69, 167-179.
[] [PMID: 29428229]
Huang, C.; Xiao, X.; Yang, Y.; Mishra, A.; Liang, Y.; Zeng, X.; Yang, X.; Xu, D.; Blackburn, M.R.; Henke, C.A.; Liu, L. MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation. J. Biol. Chem., 2017, 292(40), 16420-16439.
[] [PMID: 28726637]
Kang, H. Role of MicroRNAs in TGF-β Signaling Pathway-Mediated Pulmonary Fibrosis. Int. J. Mol. Sci., 2017, 18(12), 2527.
[PMID: 29186838]
Riquelme, I.; Tapia, O.; Leal, P.; Sandoval, A.; Varga, M.G.; Letelier, P.; Buchegger, K.; Bizama, C.; Espinoza, J.A.; Peek, R.M.; Araya, J.C.; Roa, J.C. miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway. Cell Oncol. (Dordr.), 2016, 39(1), 23-33.
[] [PMID: 26458815]
Assoian, R.K.; Komoriya, A.; Meyers, C.A.; Miller, D.M.; Sporn, M.B. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J. Biol. Chem., 1983, 258(11), 7155-7160.
[] [PMID: 6602130]
Crooks, M.G.; Fahim, A.; Naseem, K.M.; Morice, A.H.; Hart, S.P. Increased Platelet Reactivity in Idiopathic Pulmonary Fibrosis Is Mediated by a Plasma Factor.PLoS One, 2014, 9(10), e111347.
Hoying, J.B.; Yin, M.; Diebold, R.; Ormsby, I.; Becker, A.; Doetschman, T. Transforming growth factor β1 enhances platelet aggregation through a non-transcriptional effect on the fibrinogen receptor. J. Biol. Chem., 1999, 274(43), 31008-31013.
[] [PMID: 10521498]
Li, M.; Krishnaveni, M.S.; Li, C.; Zhou, B.; Xing, Y.; Banfalvi, A.; Li, A.; Lombardi, V.; Akbari, O.; Borok, Z.; Minoo, P. Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis. J. Clin. Invest., 2011, 121(1), 277-287.
[PMID: 21135509]
Ntelis, K.; Bogdanos, D.; Dimitroulas, T.; Sakkas, L.; Daoussis, D. Platelets in Systemic Sclerosis: the Missing Link Connecting Vasculopathy, Autoimmunity, and Fibrosis? Curr. Rheumatol. Rep., 2019, 21(5), 15.
[] [PMID: 30830444]
Wang, Y.; Sun, Y.; Li, D.; Zhang, L.; Wang, K.; Zuo, Y. Platelet P2Y12 Is Involved in Murine Pulmonary Metastasis.PLoS One, 2013, 8(11), e80780.
Della Latta, V.; Cecchettini, A.; Del Ry, S.; Morales, M.A. Bleomycin in the setting of lung fibrosis induction: From biological mechanisms to counteractions. Pharmacol. Res., 2015, 97, 122-130.
[PMID: 25959210]
Song, N.; Liu, J.; Shaheen, S.; Du, L.; Proctor, M.; Roman, J.; Yu, J. Vagotomy attenuates bleomycin-induced pulmonary fibrosis in mice. Sci. Rep., 2015, 5(1), 13419.
[PMID: 26289670]
Rangarajan, S.; Bone, N.B.; Zmijewska, A.A.; Jiang, S.; Park, D.W.; Bernard, K.; Locy, M.L.; Ravi, S.; Deshane, J.; Mannon, R.B.; Abraham, E.; Darley-Usmar, V.; Thannickal, V.J.; Zmijewski, J.W. Metformin reverses established lung fibrosis in a bleomycin model. Nat. Med., 2018, 24(8), 1121-1127.
[] [PMID: 29967351]
Richeldi, L.; Collard, H.R.; Jones, M.G. Idiopathic pulmonary fibrosis. Lancet, 2017, 389(10082), 1941-1952.
[] [PMID: 28365056]
Hinz, B.; Phan, S.H.; Thannickal, V.J.; Prunotto, M.; Desmoulière, A.; Varga, J.; De Wever, O.; Mareel, M.; Gabbiani, G. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am. J. Pathol., 2012, 180(4), 1340-1355.
[] [PMID: 22387320]
Handsley, M.M.; Edwards, D.R. Metalloproteinases and their inhibitors in tumor angiogenesis. Int. J. Cancer, 2005, 115(6), 849-860.
[] [PMID: 15729716]
Ohbayashi, H. Matrix metalloproteinases in lung diseases. Curr. Protein Pept. Sci., 2002, 3(4), 409-421.
[PMID: 12370004]
Gebremeskel, S.; LeVatte, T.; Liwski, R.S.; Johnston, B.; Bezuhly, M. The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer. Int. J. Cancer, 2015, 136(1), 234-240.
[] [PMID: 24798403]
Gareau, A.J.; Brien, C.; Gebremeskel, S.; Liwski, R.S.; Johnston, B.; Bezuhly, M. Ticagrelor inhibits platelet-tumor cell interactions and metastasis in human and murine breast cancer. Clin. Exp. Metastasis, 2018, 35(1-2), 25-35.
[PMID: 29322294]
Wang, Y.; Men, M.; Xie, B.; Shan, J.; Wang, C.; Liu, J.; Zheng, H.; Yang, W.; Xue, S.; Guo, C. Inhibition of PKR protects against H2O2-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation. Sci. Rep., 2016, 6(1), 38753.
[PMID: 27929137]
Liao, L.; Guo, Y.; Zhuang, X.; Li, W.; Zou, J.; Su, Q.; Zhao, J.; Liu, Y.; Liao, X.; Du, Z.; Hu, X. Immunosuppressive Effect of Ticagrelor on Dendritic Cell Function: A New Therapeutic Target of Antiplatelet Agents in Cardiovascular Disease. J. Biomed. Nanotechnol., 2018, 14(9), 1665-1673.
[PMID: 29958560]
Mao, Y.; Peng, Y.; Zeng, Q.; Cheng, L.; Wang, B.; Mao, X. A Potential Mechanism of High-Dose Ticagrelor in Modulating Platelet Activity and Atherosclerosis Mediated by Thymic Stromal Lymphopoietin Receptor.PLoS One, 2015, 10(10), e0141464.
Wang, C.; Song, X.; Li, Y.; Han, F.; Gao, S.; Wang, X.; Xie, S.; Lv, C. Low-dose paclitaxel ameliorates pulmonary fibrosis by suppressing TGF-β1/Smad3 pathway via miR-140 upregulation. PLoS One, 2013, 8(8), e70725.
[] [PMID: 23967091]

© 2023 Bentham Science Publishers | Privacy Policy