Hydrophilic Bile Acid, Ursodeoxycholic Acid Attenuates the Effect of TGF-β1 On Human Tenon’s Fibroblast
DOI:
https://doi.org/10.11113/mjfas.v17n4.2008Keywords:
Glaucoma, Ursodeoxycholic acid, Human Tenon’s FibroblastAbstract
Excessive scarring of the filtering bleb was reported post-surgery and thus lead to failed trabeculectomy. The excessive scarring occurs due to elevated level of TGF-β1 and thus leading to differentiation of tenon’s fibroblast to myofibroblast. Ursodeoxycholic acid (UDCA), the most hydrophilic bile acid, reported as beneficial agent for the treatment of ocular diseases. This study aimed to investigate whether UDCA is able to reduce the differentiation of fibroblast to myofibroblast in TGF-β1-induced human tenons fibroblast (HTF). Material and Methods: Primary HTFs were obtained and divided into untreated group, TGF-β1 treated group (20 ng/ml), UDCA treated group (100 µΜ) and TGF-β1 co-treated with UDCA (combination) group. All cells were subjected for immunostaining (α-SMA and F-actin expression), PCR array (downstream target of TGF-β1: Nf-κβ1, JUN, TIMP1, SMAD3, SMAD2) and western blot (F-actin expression). The statistically significance was set to p < 0.05 and 4 biological replicates were used. Results: The expression of α-SMA and F-actin suggest that UDCA inhibits the fibrous structure of striated actin induces by TGF-β1 as this actin were highly expressed in TGF-β only group. No significance changes in downstream target genes of TGF-β1 except for Nf-ĸβ1. Interestingly, protein expression of ERK 1/2 and gene expression of Nf-ĸβ1 were significantly decreased in combination group (TGF-β1 with UDCA) compared to TGF-β1 only group. Conclusion: UDCA attenuates the effect of TGF-β1 on human Tenon’s fibroblast by downregulating the expression of α-SMA and F-actin expression which could be mediated by ERK1/2 and NF-ĸβ1.
References
Yamanaka O, Kitano-Izutani A, Tornoyose K, Reinach PS. Pathobiology of wound healing after glaucoma filtration surgery. BMC Ophthalmology. 2015; 15(1):157-166.
Costa VP, Wilson RP, Moster MR, Schmidt CM, Gandham S. Hypotony maculopathy following the use of topical mitomycin C in glaucoma filtration surgery. Ophthalmic Surgery. 1993; 24(6): 389-394.
Mirastschijski U, Haaksma CJ, Tomasek JJ, Agren MS. Matrix metalloproteinase inhibitor GM6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. Experimental Cell Research. 2004; 299: 465-475.
Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML et al. The myofibroblast: one function, multiple origins. American Journal of Pathology. 2007; 170(6): 1807-1816.
Gan Q, Yoshida T, Li J , Owens GK. Smooth muscle cells and myofibroblasts use distinct transcriptional mechanisms for smooth muscle alpha-actin expression. Circulation Research. 2007; 101(9): 883-892.
Netto MV, Mohan RR, Ambrosio R, Hutcheon AEK, Zieske JD et al. Wound healing in the cornea: a review of refractive surgery complications and new prospects for therapy. Cornea. 2005; 24(5): 509-522.
Desmouliere A, Darby IA ,Gabbiani G. Normal and pathologic soft tissue remodeling: role of the myofibroblast, with special emphasis on liver and kidney fibrosis. Laboratory Investigation. 2003; 83(12): 1689–1707.
Gabbiani G. The myofibrolast in wound healing and fibrocontractive diseases. The Journal of Pathology. 2003; 200(4): 500-503.
Liu Y, Li Y, Li N, Teng W, Wang M, et al. TGF-β1 promotes scar fibroblasts proliferation and transdifferentiation via up-regulating MicroRNA-21. Scientific Reports. 2016; 6: 1-9.
Negmadjanov U, Godic Z, Rizvi F, Emelyanova L, Ross G, et al. TGF-β1-mediated differentiation of fibroblasts is associated with increased mitchondrial content and cellula respiration. PLoS ONE. 2015; 10: 1-12.
Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nature Clinical Practice Gastroenterology & Hepatology. 2006; 3(6): 318–328.
Duan WM, Rodrigues CM, Zhao LR, Steer CJ, Low WC. Tauroursodeoxycholic acid improves the survival and function of nigral transplants in a rat model of Parkinson’s disease. Cell Transplantation. 2002; 11(3): 195–205.
Ramalho RM, Borralho PM, Castro RE, Sola E, Steer CJ et al. Tauroursodeoxycholic acid modulates p53-mediated apoptosis in Alzheimer’s disease mutant neuroblastoma cells. Journal of Neurochemistry. 2006; 98: 1610-1618.
Von Haehling S, Schefold JC, Jankowska EA, Springer J, Vazir A, et al. Ursodeoxycholic acid in patients with chronic heart failure: a double-blinid, randomized, placebo-controlled, crossover trial. Journal of the American College of Cardiology. 2012; 59(6): 585-592
Boatright JH, Nickerson JM, Moring AG, Pardue MT. Bile acids in treatment of ocular disease. Journal of Ocular Biology, Diseases, and Informatics. 2009; 2(3): 149–159.
Clouzeau-Girard H, Guyot C, Combe C, Moronvalle-Halley V, Housset C et al. Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices. Laboratory investigation. 2006; 86: 275–285.
Ramesh K, Billson FA, Madigan MC. Effect of bile acids on fibroblast proliferation and viability. Eye (London, England). 1998; 12(4): 717-722.
Meng JP, Ceryak S, Aratsu Z, Jones L, Epstein L et al. Biphasic regulation by bile acids of dermal finroblast proliferation through regulation of cAMP production and COX-2 expression level. American Journal of Cell Physiolog. 2006; 291(202): C546-C554.
Noh SMM, Sheikh Abdul Kadir SH, Crowston JG, Subrayan V, Vasudevan S. Effects of ranibizurnab on TGF-β1 and TGF-β2 production by human tenon’s fibroblasts: an in vitro study. Molecular Vision. 2015; 21: 1191.
Xi X, McMillan DH, Lehmann GM, Sime PJ, Libby RT, et al. Ocular fibroblast diversity: implications for inflammation and ocular wound healing. Investigative Ophthalmology & Visual Science. 2011; 52(7): 4859-4865.
Skalli O & Gabbiani G. The biology of the myofibroblast relationship to wound contraction and fibrocontractive diseases. The Molecular and Cellular Biology of Wound Repair. 1988; 373-402.
Skwarek-Maruszewska A, Hotulainen P, Mattila PK, Lappalainen P. Contractility-dependent actin dynamics in cardiomyocyte sarcomeres. Journal of Cell Science. 2009; 122(12): 2119-2126.
Chhabra ES, Higgs HN. The many faces of actin: matching assembly factors with cellular structures. Nature Cell Biology. 2007; 9(10): 1110–1121.
Kaksonen M, Toret CP, Drubin DG. Harnessing actin dynamics for clathrin-mediated endocytosis. Nature Reviews Molecular Cell Biology. 2006; 7(6): 404-414.
Jester JV, Petroll WM, Barry PA, Cavanagh HD. Expression of alpha-smooth muscle (alpha-SM) actin during corneal stromal wound healing. Investigative Ophthalmology & Vision Science. 1995; 36: 809-819.
Mohan RR, Hutchein AEK, Choi R, Hong J, Lee J et al. Apoptosis, necrosis, proliferation and myofibroblast generation in the stroma following LASIK and PRK. Experimental Eye Research. 2003; 76(1): 71-87.
Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. The American Journal of Pathology. 1995; 146(1): 56–66.
Carthy JM, Stoter M, Bellomo C, Vanlandewijck M, Heldin A et al. Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation. Scientific Reports. 2016; 6: 1-14.
Hu Y, Peng J, Feng D, Chu L, Li X, et al. Role of extracellular signal-regulated kinase, p38 kinase, and activator protein-1 in transforming growth factor-β1-induced alpha smooth muscle actin expression in human fetal lung fibroblasts in vitro. Springer Link. 2006; 184(1): 33-42.
Amaral JD, Viana RJS, Ramalho RM, Steer CJ, Rodrigues CMP. Bile acids: regulation of apoptosis by ursodeoxycholic acid. Journal of Lipid Research. 2009; 50(9): 1721-1734.
Hanafi NI, Mohamed AS, Md Noor J, Abdul Hamid Hasani N, Siran R, et al. Ursodeoxycholic acid upregulates ERK and Akt in the protection of cardiomyocytes against CoCl2. Genetics and Molecular Research Journal. 2016; 15(2): 1-12.
Halilbasic E, Claudel T, Trauner M. Bile acid transporters and regulatory nuclear receptors in the liver and beyond. Journal of Hepatology. 2013; 58(1): 155-168.
Palmela I, Correia L, Silva RFM, Sasaki H, Kim KS et al. Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: an in vitro study. Frontiers in Neuroscience. 2015; 9(3): 1-11.
Philips MJ, Walker TA, Choi H, Faulkner AE, Moon K et al. Tauroursodeoxycholic acid preserves photoreceptor structure and function in the rd10 mouse through postnatal day 30. Investigative Ophthalmology & Vision Science. 2009; 49(5): 404-417.
Fernandez-Sanchez L, Lax P, Pinilla I, Martin-Nieto J, Cuenca N. Tauroursodeoxycholic acid prevents retinal degeneration in transgenic P23H rats. Investigative Ophthalmology & Visual Science. 2011; 52: 4998-5008.
Woo SJ, Kim JH, Yu HG. Ursodeoxycholic acid and tauroursodeoxycholic acid suppress choroidal neovascularization in a laser-treated rat model. Journal of Ocular Pharmacology & Therapeutics. 2010; 26(3): 223-229.
Qi HP, Wei SQ, Gao XC, Yu NN, Hu WZ et al. Ursodeoxycholic acid prevents selenite-induced oxidative stress and alleviated cataract formation: in vitro and in vivo studies. Molecular Vision. 2012; 18: 151-160.
Lim SC, Duong HQ, Parajuli KR, Han SI. Pro-apoptotic role of MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells. Oncology Reports. 2012; 28(4): 1429-1434.
Goldberg AA, Titorenko VI, Beach A, Sanderson JT. Bile acids induced apoptosis selectively in androgen-dependent and –independent prostate cancer cells. Peer Journal. 2013; 1.
Kojima M, Kamoi K, Ukimura O, Fujito A, Nakao M et al. Clinical utility of ursodeoxycholic acid in preventing flutamide induced hepatopathy in patients with prostate cancer: a preliminary study. Investigative Journal of Urology. 2016; 9(1): 2-3.
