Abstract
Among the troika of clinicopathologic features of asthma, airway remodelling has gained sufficient attention for its contribution to progressive airway narrowing. Much effort has been directed at the management of airway smooth muscle cells (ASMCs), but few attempts have proven to prevent the progression of remodelling. Recently, accumulating data have shown the anti-inflammatory/anti-proliferative potency of melatonin (a crucial neurohormone involved in many physiological and pathological processes) in diverse cells. However, no evidence has confirmed its effect on ASMCs. The present study investigates the benefits of melatonin in asthma, with an emphasis on airway remodelling. The results indicated that melatonin significantly attenuated airway hyperresponsiveness (AHR), inflammation and remodelling in a house dust mite (HDM) model. Melatonin markedly alleviated goblet cell hyperplasia/metaplasia, collagen deposition and airway smooth muscle hyperplasia/hypertrophy, implying the achievement of remodelling remission. The data obtained in vitro further revealed that melatonin notably inhibited ASMCs proliferation, VEGF synthesis and cell migration induced by PDGF, which might depend on STAT3 signalling. Moreover, melatonin remarkably relieved ASMCs contraction and reversed ASMCs phenotype switching induced by TGF-β, probably via the Akt/GSK-3β pathway. Altogether, our findings illustrated for the first time that melatonin improves asthmatic airway remodelling by balancing the phenotypic proportions of ASMCs, thus highlighting a novel purpose for melatonin as a potent option for the management of asthma.
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References
Barrett P, Bolborea M (2012) Molecular pathways involved in seasonal body weight and reproductive responses governed by melatonin. J Pineal Res 52(4):376–388. https://doi.org/10.1111/j.1600-079X.2011.00963.x
Bentley JK, Hershenson MB (2008) Airway smooth muscle growth in asthma: proliferation, hypertrophy, and migration. Proc Am Thorac Soc 5(1):89–96. https://doi.org/10.1513/pats.200705-063VS
Boldogh I, Bacsi A, Choudhury BK, Dharajiya N, Alam R, Hazra TK, Mitra S, Goldblum RM, Sur S (2005) ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation. J Clin Invest 115(8):2169–2179. https://doi.org/10.1172/jci24422
Bruderman I, Rahamimoff R (1967) Alterations in tracheobronchial smooth muscle activity following melatonin. J Appl Physiol 23(6):938–943. https://doi.org/10.1152/jappl.1967.23.6.938
Burgess JK, Johnson PR, Ge Q, Au WW, Poniris MH, McParland BE, King G, Roth M, Black JL (2003) Expression of connective tissue growth factor in asthmatic airway smooth muscle cells. Am J Respir Crit Care Med 167(1):71–77. https://doi.org/10.1164/rccm.200205-416OC
Campos FL, da Silva-Júnior FP, de Bruin VM, de Bruin PF (2004) Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med 170(9):947–951. https://doi.org/10.1164/rccm.200404-488OC
Castaneda AR, Pinkerton KE (2016) Investigating the effects of particulate matter on house dust mite and ovalbumin allergic airway inflammation in mice. Curr Protoc Toxicol 68:18.18.1–18.18.18. https://doi.org/10.1002/cptx.5
Chan V, Burgess JK, Ratoff JC, O'Connor BJ, Greenough A, Lee TH, Hirst SJ (2006) Extracellular matrix regulates enhanced eotaxin expression in asthmatic airway smooth muscle cells. Am J Respir Crit Care Med 174(4):379–385. https://doi.org/10.1164/rccm.200509-1420OC
Chao CC, Chen PC, Chiou PC, Hsu CJ, Liu PI, Yang YC, Reiter RJ, Yang SF, Tang CH (2019) Melatonin suppresses lung cancer metastasis by inhibition of epithelial-mesenchymal transition through targeting to Twist. Clin Sci (Lond) 133(5):709–722. https://doi.org/10.1042/CS20180945
Comai S, Lopez-Canul M, De Gregorio D, Posner A, Ettaoussi M, Guarnieri FC, Gobbi G (2019) Melatonin MT1 receptor as a novel target in neuropsychopharmacology: MT1 ligands, pathophysiological and therapeutic implications, and perspectives. Pharmacol Res 144:343–356. https://doi.org/10.1016/j.phrs.2019.04.015
De Bruin PF, Alves NA, De Bruin VM, Carrasco AE, Magalhães PJ (2001) The in vitro effect of melatonin on human airway smooth muscle. Am J Respir Crit Care Med 163:A637
Dekkers BG, Schaafsma D, Nelemans SA, Zaagsma J, Meurs H (2007) Extracellular matrix proteins differentially regulate airway smooth muscle phenotype and function. Am J Phys Lung Cell Mol Phys 292(6):L1405–L1413. https://doi.org/10.1152/ajplung.00331.2006
Fehrenbach H, Kasper M, Haase M, Schuh D, Müller M (1999) Differential immunolocalization of VEGF in rat and human adult lung, and in experimental rat lung fibrosis: light, fluorescence, and electron microscopy. Anat Rec 254(1):61–73. https://doi.org/10.1002/(SICI)1097-0185(19990101)254:1<61::AID-AR8>3.0.CO;2-D
Gawaziuk JP, Sheikh F, Cheng ZQ, Cattini PA, Stephens NL (2007) Transforming growth factor-beta as a differentiating factor for cultured smooth muscle cells. Eur Respir J 30(4):643–652. https://doi.org/10.1183/09031936.00141805
Goldsmith AM, Bentley JK, Zhou L, Jia Y, Bitar KN, Fingar DC, Hershenson MB (2006) Transforming growth factor-beta induces airway smooth muscle hypertrophy. Am J Respir Cell Mol Biol 34(2):247–254. https://doi.org/10.1165/rcmb.2005-0166OC
Goncharova EA, Billington CK, Irani C, Vorotnikov AV, Tkachuk VA, Penn RB, Krymskaya VP, Panettieri RA Jr (2003) Cyclic AMP-mobilizing agents and glucocorticoids modulate human smooth muscle cell migration. Am J Respir Cell Mol Biol 29:19–27. https://doi.org/10.1165/rcmb.2002-0254OC
Goncharova EA, Goncharov DA, Krymskaya VP (2006) Assays for in vitro monitoring of human airway smooth muscle (ASM) and human pulmonary arterial vascular smooth muscle (VSM) cell migration. Nat Protoc 1(6):2933–2939. https://doi.org/10.1038/nprot.2006.434
Gosens R, Meurs H, Bromhaar MM, McKay S, Nelemans SA, Zaagsma J (2002) Functional characterization of serum- and growth factor-induced phenotypic changes in intact bovine tracheal smooth muscle. Br J Pharmacol 137(4):459–466. https://doi.org/10.1038/sj.bjp.0704889
Gumral N, Caliskan S, Ozgüner F, Kaleli S, Akkaya A, Yilmaz H, Sen S (2009) Melatonin levels and enzymatic antioxidant defense system decrease in blood of patients with bronchial asthma. Toxicol Ind Health 25(6):411–416. https://doi.org/10.1177/0748233709106625
Hirst SJ, Twort CH, Lee TH (2000) Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. Am J Respir Cell Mol Biol 23(3):335–344. https://doi.org/10.1165/ajrcmb.23.3.3990
Hirst SJ, Hallsworth MP, Peng Q, Lee TH (2002) Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1beta and is mediated by the interleukin-4 receptor alpha-chain. Am J Respir Crit Care Med 165(8):1161–1171. https://doi.org/10.1164/ajrccm.165.8.2107158
Hou C, Kong J, Liang Y, Huang H, Wen H, Zheng X, Wu L, Chen Y (2015) HMGB1 contributes to allergen-induced airway remodeling in a murine model of chronic asthma by modulating airway inflammation and activating lung fibroblasts. Cell Mol Immunol 12(4):409–423. https://doi.org/10.1038/cmi.2014.60
Jin H, Wang Y, Zhou L, Liu L, Zhang P, Deng W, Yuan Y (2014) Melatonin attenuates hypoxic pulmonary hypertension by inhibiting the inflammation and the proliferation of pulmonary arterial smooth muscle cells. J Pineal Res 57(4):442–450. https://doi.org/10.1111/jpi.12184
Johnson PR, Roth M, Tamm M, Hughes M, Ge Q, King G, Burgess JK, Black JL (2001) Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med 164(3):474–477. https://doi.org/10.1164/ajrccm.164.3.2010109
Johnson JR, Wiley RE, Fattouh R, Swirski FK, Gajewska BU, Coyle AJ, Gutierrez-Ramos JC, Ellis R, Inman MD, Jordana M (2004) Continuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling. Am J Respir Crit Care Med 169(3):378–385. https://doi.org/10.1164/rccm.200308-1094OC
Karasu-Minareci E, Kaya Y, Belgin Yildirim F (2012) The achilles heel in melatonin: asthma. Iran J Allergy Asthma Immunol 11(3):246–252
Kerzerho J, Maazi H, Speak AO, Szely N, Lombardi V, Khoo B, Geryak S, Lam J, Soroosh P, Van Snick J, Akbari O (2013) Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity. J Allergy Clin Immunol 131(4):1048–1057, e2. https://doi.org/10.1016/j.jaci.2012.09.027
Knox AJ, Corbett L, Stocks J, Holland E, Zhu YM, Pang L (2001) Human airway smooth muscle cells secrete vascular endothelial growth factor: up-regulation by bradykinin via a protein kinase C and prostanoid-dependent mechanism. FASEB J 15(13):2480–2488. https://doi.org/10.1096/fj.01-0256com
Konno R, Yamakawa H, Utsunomiya H, Ito K, Sato S, Yajima A (2000) Expression of survivin and Bcl-2 in the normal human endometrium. Mol Hum Reprod 6(6):529–534. https://doi.org/10.1093/molehr/6.6.529
Lee CG, Link H, Baluk P, Homer RJ, Chapoval S, Bhandari V, Kang MJ, Cohn L, Kim YK, McDonald DM, Elias JA (2004) Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med 10(10):1095–1103. https://doi.org/10.1038/nm1105
Lu CD, Altieri DC, Tanigawa N (1998) Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res 58(9):1808–1812
Lv J, Sun B, Mai Z, Jiang M, Du J (2017) STAT3 potentiates the ability of airway smooth muscle cells to promote angiogenesis by regulating VEGF signalling. Exp Physiol 102(5):598–606. https://doi.org/10.1113/ep086136
Ma Y, Zhang JX, Liu YN, Ge A, Gu H, Zha WJ, Zeng XN, Huang M (2016) Caffeic acid phenethyl ester alleviates asthma by regulating the airway microenvironment via the ROS-responsive MAPK/Akt pathway. Free Radic Biol Med 101:163–175. https://doi.org/10.1016/j.freeradbiomed
Ma Z, Liu D, Di S, Zhang Z, Li W, Zhang J, Xu L, Guo K, Zhu Y, Li X, Han J, Yan X (2017) Histone deacetylase 9 downregulation decreases tumor growth and promotes apoptosis in non-small cell lung cancer after melatonin treatment. J Pineal Res 15:e12587. https://doi.org/10.1111/jpi.12587
Mauriz JL, Collado PS, Veneroso C, Reiter RJ, Gonzalez-Gallego J (2013) A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J Pineal Res 54(1):1–14. https://doi.org/10.1111/j.1600-079X.2012.01014.x
Moore PE, Church TL, Chism DD, Panettieri RA Jr, Shore SA (2002) IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK. Am J Phys Lung Cell Mol Phys 282(4):L847–L853. https://doi.org/10.1152/ajplung.00245.2001
Mühlfeld C, Hegermann J, Wrede C, Ochs M (2015) A review of recent developments and applications of morphometry/stereology in lung research. Am J Phys Lung Cell Mol Phys 309(6):L526–L536. https://doi.org/10.1152/ajplung.00047.2015
Oenema TA, Smit M, Smedinga L, Racké K, Halayko AJ, Meurs H, Gosens R (2012) Muscarinic receptor stimulation augments TGF-beta1-induced contractile protein expression by airway smooth muscle cells. Am J Phys Lung Cell Mol Phys 303(7):L589–L597. https://doi.org/10.1152/ajplung.00400.2011
Parameswaran K, Cox G, Radford K, Janssen LJ, Sehmi R, O’Byrne PM (2002) Cysteinyl leukotrienes promote human airway smooth muscle migration. Am J Respir Crit Care Med 166:738–742. https://doi.org/10.1164/rccm.200204-291OC
Rahamimoff R, Bruderman I, Golshani G (1965) Effect of melatonin on 5-hydroxytryptamine induced contraction of isolated cat trachea. Life Sci 4:2281–2287
Redhu NS, Shan L, Movassagh H, Gounni AS (2013) Thymic stromal lymphopoietin induces migration in human airway smooth muscle cells. Sci Rep 3:2301. https://doi.org/10.1038/srep02301
Reiter RJ (1991) Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 12(2):151–180. https://doi.org/10.1210/edrv-12-2-151
Salter B, Pray C, Radford K, Martin JG, Nair P (2017) Regulation of human airway smooth muscle cell migration and relevance to asthma. Respir Res 18(1):156. https://doi.org/10.1186/s12931-017-0640-8
Schaafsma D, Gosens R, Bos IS, Meurs H, Zaagsma J, Nelemans SA (2004) Allergic sensitization enhances the contribution of Rho-kinase to airway smooth muscle contraction. Br J Pharmacol 143(4):477–484. https://doi.org/10.1038/sj.bjp.0705903
Shin IS, Park JW, Shin NR, Jeon CM, Kwon OK, Lee MY, Kim HS, Kim JC, Oh SR, Ahn KS (2014) Melatonin inhibits MUC5AC production via suppression of MAPK signaling in human airway epithelial cells. J Pineal Res 56(4):398–407. https://doi.org/10.1111/jpi.12127
Tam CW, Mo CW, Yao KM, Shiu SY (2007) Signaling mechanisms of melatonin in antiproliferation of hormone-refractory 22Rv1 human prostate cancer cells: implications for prostate cancer chemoprevention. J Pineal Res 42(2):191–202. https://doi.org/10.1111/j.1600-079X.2006.00406.x
Tarocco A, Caroccia N, Morciano G, Wieckowski MR, Ancora G, Garani G, Pinton P (2019) Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis 10(4):317. https://doi.org/10.1038/s41419-019-1556-7
Weekley LB (1995) Influence of melatonin on bovine pulmonary vascular and bronchial airway smooth muscle tone. Clin Auton Res 5(1):53–56
Wright DB, Trian T, Siddiqui S, Pascoe CD, Johnson JR, Dekkers BG, Dakshinamurti S, Bagchi R, Burgess JK, Kanabar V, Ojo OO (2013) Phenotype modulation of airway smooth muscle in asthma. Pulm Pharmacol Ther 26(1):42–49. https://doi.org/10.1016/j.pupt.2012.08.005
Zuyderduyn S, Sukkar MB, Fust A, Dhaliwal S, Burgess JK (2008) Treating asthma means treating airway smooth muscle cells. Eur Respir J 32(2):265–274. https://doi.org/10.1183/09031936.00051407
Funding
This work was supported by the Jiangsu Province Special Program for Young Medical Talent (QNRC2016599), the National Natural Science Foundation of China (NSFC) (Grant No. 81700028), the Changzhou International Science and Technology Collaboration Program (CZ20110021) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, JX10231802).
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Yu, Q., Yu, X., Zhong, X. et al. Melatonin modulates airway smooth muscle cell phenotype by targeting the STAT3/Akt/GSK-3β pathway in experimental asthma. Cell Tissue Res 380, 129–142 (2020). https://doi.org/10.1007/s00441-019-03148-x
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DOI: https://doi.org/10.1007/s00441-019-03148-x