Introduction: Respiratory viral infection in childhood is closely associated with asthmatic attacks. Of all predisposing factors, viral infection is the primary contributor to acute childhood asthma exacerbations. However, the mechanisms involved in viral asthma are unclear. This study attempted to provide insights into molecular mechanisms in respiratory virus-induced acute asthma exacerbations. Methods: House dust mite (HDM) was given by intranasal administration to induce asthma in mice. Poly(I:C) was used to mimic the viral infection. A selective YAP inhibitor, verteporfin (VP), was used to investigate the role of the YAP/FOXM1 pathway. The expression of YAP, FOXM1, cytokines, and inflammatory cells in lung tissue, and bronchoalveolar lavage fluid (BALF) was determined using RT-PCR, immunohistochemical, ELISA, and flow cytometry studies. The methacholine challenge assesses airway hyperresponsiveness. In 16HBE cell experiments, we selectively inhibited YAP and FOXM1 by VP and RCM1, respectively, and detected the expression of YAP and FOXM1. Results: The experimental studies have confirmed the YAP/FOXM1 pathway plays a vital role in the differentiation and proliferation of airway club cells into goblet cells and lung inflammation. Poly(I:C) upregulated the expression of FOXM1 by activating transcription factor YAP in mice airway epithelial cells and then promoted the expression of downstream transcription factors SPDEF/MUC5AC, resulting in airway mucus hypersecretion and hyperresponsiveness. In addition, Poly(I:C) facilitates the expression of inflammatory factors in lung tissue. All of these events induce asthma exacerbations. The in vitro studies have confirmed that YAP positively regulates FOXM1 in airway epithelial cells. Conclusion: Poly(I:C) promotes airway epithelial goblet cell hyperplasia, mucus hypersecretion, and airway hyperresponsiveness. It also upregulates the expression of inflammatory factors in lung tissue and BALF in asthmatic mice by the YAP/FOXM1 pathway, resulting in asthma attacks.

Keywords:
YAP, Poly(I:C), Asthma, Airway inflammation, Goblet cell hyperplasia
1.
Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev. 2011 Jul;242(1):10–30.
2.
Ramsahai JM, Hansbro PM, Wark PAB. Mechanisms and management of asthma exacerbations. Am J Respir Crit Care Med. 2019 Feb 15;199(4):423–32.
3.
Caffrey Osvald E, Bower H, Lundholm C, Larsson H, Brew BK, Almqvist C. Asthma and all-cause mortality in children and young adults: a population-based study. Thorax. 2020 Dec;75(12):1040–6.
4.
Zheng XY, Xu YJ, Guan WJ, Lin LF. Regional, age and respiratory-secretion-specific prevalence of respiratory viruses associated with asthma exacerbation: a literature review. Arch Virol. 2018 Apr;163(4):845–53.
5.
Homma T, Fukuda Y, Uchida Y, Uno T, Jinno M, Kishino Y, et al. Inhibition of virus-induced cytokine production from airway epithelial cells by the late addition of budesonide. Medicina. 2020 Feb 27;56(3):98.
6.
Bhushan B, Homma T, Norton JE, Sha Q, Siebert J, Gupta DS, et al. Suppression of epithelial signal transducer and activator of transcription 1 activation by extracts of Aspergillus fumigatus. Am J Respir Cell Mol Biol. 2015 Jul;53(1):87–95.
7.
Jartti T, Bønnelykke K, Elenius V, Feleszko W. Role of viruses in asthma. Semin Immunopathol. 2020 Feb;42(1):61–74.
8.
Evans CM, Raclawska DS, Ttofali F, Liptzin DR, Fletcher AA, Harper DN, et al. The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat Commun. 2015;6:6281.
9.
Zanin M, Baviskar P, Webster R, Webby R. The interaction between respiratory pathogens and mucus. Cell Host Microbe. 2016;19(2):159–68.
10.
Craig SS, Dalziel SR, Powell CV, Graudins A, Babl FE, Lunny C. Interventions for escalation of therapy for acute exacerbations of asthma in children: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2020 Aug 5;8(8):CD012977.
11.
Sun L, Ren X, Wang IC, Pradhan A, Zhang Y, Flood HM, et al. The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice. Sci Signal. 2017 Apr 18;10(475):eaai8583.
12.
Deng H, Sun Y, Wang W, Li M, Yuan T, Kong W, et al. The hippo pathway effector Yes-associated protein promotes epithelial proliferation and remodeling in chronic rhinosinusitis with nasal polyps. Allergy. 2019 Apr;74(4):731–42.
13.
Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163(4):811–28.
14.
Mizuno T, Murakami H, Fujii M, Ishiguro F, Tanaka I, Kondo Y, et al. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes. Oncogene. 2012;31(49):5117–22.
15.
Nilsson MB, Sun H, Robichaux J, Pfeifer M, McDermott U, Travers J, et al. A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components. Sci Transl Med. 2020 Sep 2;12(559):eaaz4589.
16.
Wang X, Ha T, Liu L, Hu Y, Kao R, Kalbfleisch J, et al. TLR3 mediates repair and regeneration of damaged neonatal heart through glycolysis dependent YAP1 regulated miR-152 expression. Cell Death Differ. 2018 May;25(5):966–82.
17.
Ren X, Zhang Y, Snyder J, Cross ER, Shah TA, Kalin TV, et al. Forkhead box M1 transcription factor is required for macrophage recruitment during liver repair. Mol Cell Biol. 2010 Nov;30(22):5381–93.
18.
Ren X, Ustiyan V, Pradhan A, Cai Y, Havrilak JA, Bolte CS, et al. FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells. Circ Res. 2014 Sep 26;115(8):709–20.
19.
Hoffmann AD, Yang XH, Burnicka-Turek O, Bosman JD, Ren X, Steimle JD, et al. Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation. PLoS Genet. 2014 Oct 30;10(10):e1004604.
20.
Kalinichenko VV, Gusarova GA, Shin B, Costa RH. The forkhead box F1 transcription factor is expressed in brain and head mesenchyme during mouse embryonic development. Gene Expr Patterns. 2003 May;3(2):153–8.
21.
Xu J, Liu H, Lan Y, Aronow BJ, Kalinichenko VV, Jiang R. A shh-foxf-fgf18-shh molecular circuit regulating palate development. PLoS Genet. 2016 Jan 8;12(1):e1005769.
22.
Yao Z, Fu Y. Glycyrrhizic acid restrains airway inflammation and remodeling in asthma via the TGF-β1/Smad signaling pathway. Exp Ther Med. 2021 May;21(5):461.
23.
Zhou J, Zhang N, Zhang W, Lu C, Xu F. The YAP/HIF-1α/miR-182/EGR2 axis is implicated in asthma severity through the control of Th17 cell differentiation. Cell Biosci. 2021 May 12;11(1):84.
24.
Pradhan A, Ustiyan V, Zhang Y, Kalin TV, Kalinichenko VV. Forkhead transcription factor FoxF1 interacts with Fanconi anemia protein complexes to promote DNA damage response. Oncotarget. 2016 Jan 12;7(2):1912–26.
25.
Xia H, Ren X, Bolte CS, Ustiyan V, Zhang Y, Shah TA, et al. Foxm1 regulates resolution of hyperoxic lung injury in newborns. Am J Respir Cell Mol Biol. 2015 May;52(5):611–21.
26.
Hoggatt AM, Kim JR, Ustiyan V, Ren X, Kalin TV, Kalinichenko VV, et al. The transcription factor Foxf1 binds to serum response factor and myocardin to regulate gene transcription in visceral smooth muscle cells. J Biol Chem. 2013 Oct 4;288(40):28477–87.
27.
Zhang Y, Xu B, Luan B, Zhang Y, Wang X, Xiong X, et al. Tumor-derived MDSCs inhibit airway remodeling in asthmatic mice through regulating IL-10 and IL-12. Am J Transl Res. 2019 Jul 15;11(7):4192–202.
28.
Wu J, Qin W, Wang Y, Sadik A, Liu J, Wang Y, et al. SPDEF is overexpressed in gastric cancer and triggers cell proliferation by forming a positive regulation loop with FoxM1. J Cell Biochem. 2018 Nov;119(11):9042–54.
29.
Koh KD, Siddiqui S, Cheng D, Bonser LR, Sun DI, Zlock LT, et al. Efficient RNP-directed human gene targeting reveals SPDEF is required for IL-13-induced mucostasis. Am J Respir Cell Mol Biol. 2020 Mar;62(3):373–81.
30.
Chen G, Volmer AS, Wilkinson KJ, Deng Y, Jones LC, Yu D, et al. Role of spdef in the regulation of Muc5b expression in the airways of naive and mucoobstructed mice. Am J Respir Cell Mol Biol. 2018 Sep;59(3):383–96.
31.
Mthembu N, Ikwegbue P, Brombacher F, Hadebe S. Respiratory viral and bacterial factors that influence early childhood asthma. Front Allergy. 2021 Jul 22;2:692841.
32.
Steinke JW, Borish L. Immune responses in rhinovirus-induced asthma exacerbations. Curr Allergy Asthma Rep. 2016 Nov;16(11):78.
33.
Liu L, Zhai C, Pan Y, Zhu Y, Shi W, Wang J, et al. Sphingosine-1-phosphate induces airway smooth muscle cell proliferation, migration, and contraction by modulating Hippo signaling effector YAP. Am J Physiol Lung Cell Mol Physiol. 2018 Oct 1;315(4):L609–21.
34.
Fu J, Zheng M, Zhang X, Zhang Y, Chen Y, Li H, et al. Fibulin-5 promotes airway smooth muscle cell proliferation and migration via modulating Hippo-YAP/TAZ pathway. Biochem Biophys Res Commun. 2017 Nov 18;493(2):985–91.
35.
Isfort I, Cyra M, Elges S, Kailayangiri S, Altvater B, Rossig C, et al. SS18-SSX-Dependent YAP/TAZ signaling in synovial sarcoma. Clin Cancer Res. 2019 Jun 15;25(12):3718–31.
36.
Weiler SME, Pinna F, Wolf T, Lutz T, Geldiyev A, Sticht C, et al. Induction of chromosome instability by activation of yes-associated protein and forkhead box M1 in liver cancer. Gastroenterology. 2017 Jun;152(8):2037–51.e22.
37.
Lafkas D, Shelton A, Chiu C, de Leon Boenig G, Chen Y, Stawicki SS, et al. Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung. Nature. 2015 Dec 3;528(7580):127–31.
38.
Lange AW, Sridharan A, Xu Y, Stripp BR, Perl AK, Whitsett JA. Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung. J Mol Cell Biol. 2015 Feb;7(1):35–47.
39.
Kim SL, Choi HS, Kim JH, Lee DS. The antiasthma medication ciclesonide suppresses breast cancer stem cells through inhibition of the glucocorticoid receptor signaling-dependent YAP pathway. Molecules. 2020 Dec 19;25(24):6028.
40.
Rajput C, Han M, Bentley JK, Lei J, Ishikawa T, Wu Q, et al. Enterovirus D68 infection induces IL-17-dependent neutrophilic airway inflammation and hyperresponsiveness. JCI Insight. 2018 Aug 23;3(16):e121882.
41.
Jia Z, Bao K, Wei P, Yu X, Zhang Y, Wang X, et al. EGFR activation-induced decreases in claudin1 promote MUC5AC expression and exacerbate asthma in mice. Mucosal Immunol. 2021 Jan;14(1):125–34.
42.
El-Hashim AZ, Khajah MA, Renno WM, Babyson RS, Uddin M, Benter IF, et al. Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model. Sci Rep. 2017 Aug 30;7(1):9919.
43.
Chen G, Korfhagen TR, Xu Y, Kitzmiller J, Wert SE, Maeda Y, et al. SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production. J Clin Invest. 2009 Oct;119(10):2914–24.
44.
LaCanna R, Liccardo D, Zhang P, Tragesser L, Wang Y, Cao T, et al. Yap/Taz regulate alveolar regeneration and resolution of lung inflammation. J Clin Invest. 2019 Apr 15;129(5):2107–22.
45.
Deng H, Li M, Zheng R, Qiu H, Yuan T, Wang W, et al. YAP promotes cell proliferation and EpitheliumDerived cytokine expression via NF-κB pathway in nasal polyps. J Asthma Allergy. 2021;14:839–50.
46.
Wu D, Jiang W, Liu C, Liu L, Li F, Ma X, et al. CTNNAL1 participates in the regulation of mucus overproduction in HDM-induced asthma mouse model through the YAP-ROCK2 pathway. J Cell Mol Med. 2022;26(5):1656–71.
© 2023 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2023
You do not currently have access to this content.