Nội dung được dịch bởi AI, chỉ mang tính chất tham khảo
Peptit giải phóng gastrin kích thích phản ứng xơ hóa ở tế bào MRC5 và tăng sinh ở tế bào A549
Tóm tắt
Xơ phổi vô căn (IPF) là một bệnh lý phổi phức tạp, trong đó sự hình thành mô sẹo được gây ra bởi nhiều phân tử khác nhau. Peptit giải phóng gastrin (GRP) được tiết ra từ các tế bào nội tiết thần kinh phổi, đại thực bào phế nang và một số đầu dây thần kinh trong phổi. Vai trò tiềm năng của GRP trong IPF vẫn chưa rõ ràng. Chúng tôi nhằm mục đích điều tra phản ứng xơ hóa với GRP ở mức độ tế bào trong các dòng tế bào MRC5 và A549. Các hiệu ứng tăng sinh và xơ hóa của GRP trên các tế bào này được đánh giá bằng cách sử dụng BrdU, phương pháp miễn dịch phân tích, miễn dịch huỳnh quang và qRT-PCR cho các phân tử liên quan đến phân hóa myofibroblast, TGF-β và tín hiệu Wnt. Tất cả các liều GRP đều làm tăng lượng BrdU được đưa vào các tế bào A549. Ngược lại, lượng BrdU tăng lên ở các tế bào MRC5 trong 24 giờ đầu tiên, nhưng sau đó giảm dần đến 72 giờ. GRP không kích thích sự chuyển đổi biểu mô-mesenchymal ở các tế bào A549, thay vào đó, nó kích thích sự phân hóa của các tế bào MRC5 thành myofibroblast. Hơn nữa, GRP đã kích thích sự biểu hiện gene và protein của p-Smad2/3 và Smad4, và giảm mức độ Smad7 ở các tế bào MRC5. Ngoài ra, GRP đã làm giảm mức protein Wnt5a và kích thích sự hoạt hóa β-catenin bằng cách tăng mức độ protein Wnt4, Wnt7a và β-catenin. GRP đã gây ra sự phân hóa myofibroblast bằng cách kích thích các con đường TGF-β và Wnt thông qua tín hiệu ngoại tiết và tự tiết trong các tế bào MRC5. Kết luận, GRP có thể dẫn đến xơ phổi do các tác động tăng sinh và xơ hóa của nó lên các tế bào fibroblast phổi. Việc ngăn chặn sự kích hoạt tín hiệu trung gian GRP có thể được xem như một phương pháp điều trị cho các bệnh phổi xơ hóa.
Từ khóa
Tài liệu tham khảo
Clarke DL, Carruthers AM, Mustelin T, Murray LA. Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes. Fibrogenesis Tissue Repair. 2013;6:20.
Philp CJ, Siebeke I, Clements D, Miller S, Habgood A, John AE, Navaratnam V, Hubbard RB, Jenkins G, Johnson SR. Extracellular matrix cross-linking enhances fibroblast growth and protects against matrix proteolysis in lung fibrosis. Am J Respir Cell Mol Biol. 2018;58:594–603.
Oztay F. The responses of some pulmonary cells neuroendocrine experimental condition in the lung of Rana ridibunda. Anim Biol. 2006;56:373–82.
Brouns I, Oztay F, Pintelon I, De Proost I, Lembrechts R, Timmermans JP, Adriaensen D. Neurochemical pattern of the complex innervation of neuroepithelial bodies in mouse lungs. Histochem Cell Biol. 2009;131:55–74.
Reynolds SD, Hong KU, Giangreco A, Mango GW, Guron C, Morimoto Y, Stripp BR. Conditional clara cell ablation reveals a self-renewing progenitor function of pulmonary neuroendocrine cells. Am J Physiol Lung Cell Mol Physiol. 2000;278:L1256–63.
Polak JM, Bloom SR. Regulatory peptides of the gastrointestinal and respiratory tracts. Arch Int Pharmacodyn Ther. 1986;280:16–49.
Bodegas ME, Montuenga LM, Sesma P. Neuroendocrine diffuse system of the respiratory tract of Rana temporaria: an immunocytochemical study. Gen Comp Endocrinol. 1995;100:145–61.
Oztay F, Tabakoglu-Oguz A. Neuroepithelial endocrine cells in the lung of Rana ridibunda: an immunohistochemical study. Turk J Biol. 2003;27:65–72.
Cutz E. Introduction to pulmonary neuroendocrine cell system, structure-function correlations. Microsc Res Tech. 1997;37:1–3.
Oztay F. The functional morphology of the pulmonary neuroendocrine cells in the lung of larval and adult Rana ridibunda. Eur J Biol. 2008;67:145–51.
Liu J, Song N, Tian S, Yu J. Neuroepithelial body increases in bleomycin-treated mice. Respir Physiol Neurobiol. 2014;193:52–4.
Gosney JR, Sissons MC, Allibone RO, Blakey AF. Pulmonary endocrine cells in chronic bronchitis and emphysema. J Pathol. 1989;157:127–33.
Ito T, Ogura T, Ogawa N, Udaka N, Hayashi H, Inayama Y, Yazawa T, Kitamura H. Modulation of pulmonary neuroendocrine cells in idiopathic interstitial pneumonia. Histol Histopathol. 2002;17:1121–7.
Emanuel RL, Torday JS, Mu Q, Asokananthan N, Sikorski KA, Sunday ME. Bombesin-like peptides and receptors in normal fetal baboon lung: roles in lung growth and maturation. Am J Phys. 1999;277:L1003–17.
Ashour K, Shan L, Lee JH, Schlicher W, Wada K, Wada E, Sunday ME. Bombesin inhibits alveolarization and promotes pulmonary fibrosis in newborn mice. Am J Respir Crit Care Med. 2006;173:1377–85.
Zhou S, Nissao E, Jackson IL, Leong W, Dancy L, Cuttitta F, Vujaskovic Z, Sunday ME. Radiation-induced lung injury is mitigated by blockade of gastrin-releasing peptide. Am J Pathol. 2013;182:1248–54.
Konigshoff M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, et al. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest. 2009;119:772–87.
Yilmaz O, Oztay F, Kayalar O. Dasatinib attenuated bleomycin-induced pulmonary fibrosis in mice. Growth Factors. 2015;33:366–75.
Ramos C, Montano M, Garcia-Alvarez J, Ruiz V, Uhal BD, Selman M, Pardo A. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. Am J Respir Cell Mol Biol. 2001;24:591–8.
Xia H, Diebold D, Nho R, Perlman D, Kleidon J, Kahm J, Avdulov S, Peterson M, Nerva J, Bitterman P, Henke C. Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J Exp Med. 2008;205:1659–72.
Vuga LJ, Ben-Yehudah A, Kovkarova-Naumovski E, Oriss T, Gibson KF, Feghali-Bostwick C, Kaminski N. WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. Am J Respir Cell Mol Biol. 2009;41:583–9.
Muir D, Varon S, Manthorpe M. An enzyme-linked immunosorbent assay for bromodeoxyuridine incorporation using fixed microcultures. Anal Biochem. 1990;185:377–82.
Tsutsumi Y, Osamura RY, Watanabe K, Yanaihara N. Simultaneous immunohistochemical localization of gastrin releasing peptide (GRP) and calcitonin (CT) in human bronchial endocrine-type cells. Virchows Arch A Pathol Anat Histopathol. 1983;400:163–71.
Lemaire I, Jones S, Khan MF. Bombesin-like peptides in alveolar macrophage: increased release in pulmonary inflammation and fibrosis. Neuropeptides. 1991;20:63–72.
Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006;103:13180–5.
Marmai C, Sutherland RE, Kim KK, Dolganov GM, Fang X, Kim SS, Jiang S, Golden JA, Hoopes CW, Matthay MA, et al. Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2011;301:L71–8.
Chen X, Peng H, Xiao J, Guan A, Xie B, He B, Chen Q. Benzo(a)pyrene enhances the EMT-associated migration of lung adenocarcinoma A549 cells by upregulating Twist1. Oncol Rep. 2017;38:2141–7.
Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res. 2005;6:56.
Li XW, Li XH, Du J, Li D, Li YJ, Hu CP. Calcitonin gene-related peptide down-regulates bleomycin-induced pulmonary fibrosis. Can J Physiol Pharmacol. 2016;94:1315–24.
Jaeger N, Czepielewski RS, Bagatini M, Porto BN, Bonorino C. Neuropeptide gastrin-releasing peptide induces PI3K/reactive oxygen species-dependent migration in lung adenocarcinoma cells. Tumour Biol. 2017;39:1010428317694321.
Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest. 1997;100:768–76.
Warburton D, Shi W, Xu B. TGF-beta-Smad3 signaling in emphysema and pulmonary fibrosis: an epigenetic aberration of normal development? Am J Physiol Lung Cell Mol Physiol. 2013;304:L83–5.
Ovet H, Oztay F. The copper chelator tetrathiomolybdate regressed bleomycin-induced pulmonary fibrosis in mice, by reducing lysyl oxidase expressions. Biol Trace Elem Res. 2014;162:189–99.
Oruqaj G, Karnati S, Vijayan V, Kotarkonda LK, Boateng E, Zhang W, Ruppert C, Gunther A, Shi W, Baumgart-Vogt E. Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-beta signaling. Proc Natl Acad Sci U S A. 2015;112:E2048–57.
Fernandez IE, Eickelberg O. The impact of TGF-beta on lung fibrosis: from targeting to biomarkers. Proc Am Thorac Soc. 2012;9:111–6.
Khalil N, O'Connor RN, Flanders KC, Unruh H. TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study. Am J Respir Cell Mol Biol. 1996;14:131–8.
Kayalar O, Oztay F. Retinoic acid induced repair in the lung of adult hyperoxic mice, reducing transforming growth factor-beta1 (TGF-beta1) mediated abnormal alterations. Acta Histochem. 2014;116:810–9.
Ghosh AK, Yuan W, Mori Y, Varga J. Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-beta involves functional cooperation with p300/CBP transcriptional coactivators. Oncogene. 2000;19:3546–55.
Li YJ, Azuma A, Usuki J, Abe S, Matsuda K, Sunazuka T, Shimizu T, Hirata Y, Inagaki H, Kawada T, et al. EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-beta signaling in lung fibroblasts. Respir Res. 2006;7:16.
Zhao J, Shi W, Wang YL, Chen H, Bringas P Jr, Datto MB, Frederick JP, Wang XF, Warburton D. Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol. 2002;282:L585–93.
Bellaye PS, Wettstein G, Burgy O, Besnard V, Joannes A, Colas J, Causse S, Marchal-Somme J, Fabre A, Crestani B, et al. The small heat-shock protein alphaB-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis. J Pathol. 2014;232:458–72.
Nakao A, Fujii M, Matsumura R, Kumano K, Saito Y, Miyazono K, Iwamoto I. Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J Clin Invest. 1999;104:5–11.
Chilosi M, Poletti V, Zamo A, Lestani M, Montagna L, Piccoli P, Pedron S, Bertaso M, Scarpa A, Murer B, et al. Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol. 2003;162:1495–502.
Selman M, Pardo A, Barrera L, Estrada A, Watson SR, Wilson K, Aziz N, Kaminski N, Zlotnik A. Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2006;173:188–98.
Shi J, Li F, Luo M, Wei J, Liu X. Distinct roles of Wnt/beta-catenin signaling in the pathogenesis of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Mediat Inflamm. 2017;2017:3520581.
Yang IV, Burch LH, Steele MP, Savov JD, Hollingsworth JW, McElvania-Tekippe E, Berman KG, Speer MC, Sporn TA, Brown KK, et al. Gene expression profiling of familial and sporadic interstitial pneumonia. Am J Respir Crit Care Med. 2007;175:45–54.
Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, et al. Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat Commun. 2012;3:735.
Wang Y, Liu J, Chen J, Feng T, Guo Q. MiR-29 mediates TGFbeta 1-induced extracellular matrix synthesis through activation of Wnt/beta -catenin pathway in human pulmonary fibroblasts. Technol Health Care. 2015;23(Suppl 1):S119–25.
Zhang ZM, Gu P, Yi XH, Fang X, Zeng Y, Zhang SX, Zhu XY, Zhang YD, Gu J, Qiu WZ, Zhang L. Effects of 1, 25 (OH)2D3 on bleomycin-induced pulmonary fibrosis in mice. Zhonghua Jie He He Hu Xi Za Zhi. 2013;36:814–20.
Kovacs T, Csongei V, Feller D, Ernszt D, Smuk G, Sarosi V, Jakab L, Kvell K, Bartis D, Pongracz JE. Alteration in the Wnt microenvironment directly regulates molecular events leading to pulmonary senescence. Aging Cell. 2014;13:838–49.
Martin-Medina A, Lehmann M, Burgy O, Hermann S, Baarsma HA, Wagner DE, De Santis MM, Ciolek F, Hofer TP, Frankenberger M, et al. Increased extracellular vesicles mediate WNT-5A signaling in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2018;198(12):1527-38.
Newman DR, Sills WS, Hanrahan K, Ziegler A, Tidd KM, Cook E, Sannes PL. Expression of WNT5A in idiopathic pulmonary fibrosis and its control by TGF-beta and WNT7B in human lung fibroblasts. J Histochem Cytochem. 2016;64:99–111.
Guan S, Zhou J. Frizzled-7 mediates TGF-beta-induced pulmonary fibrosis by transmitting non-canonical Wnt signaling. Exp Cell Res. 2017;359:226–34.
Colwell AS, Krummel TM, Longaker MT, Lorenz HP. Wnt-4 expression is increased in fibroblasts after TGF-beta1 stimulation and during fetal and postnatal wound repair. Plast Reconstr Surg. 2006;117:2297–301.
Meuten T, Hickey A, Franklin K, Grossi B, Tobias J, Newman DR, Jennings SH, Correa M, Sannes PL. WNT7B in fibroblastic foci of idiopathic pulmonary fibrosis. Respir Res. 2012;13:62.
Salazar KD, Lankford SM, Brody AR. Mesenchymal stem cells produce Wnt isoforms and TGF-beta1 that mediate proliferation and procollagen expression by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol. 2009;297:L1002–11.