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Yet, how to protect human airways, short of deep and sustained reductions in greenhouse gas emissions, remains unclear. Here, we find by climate modeling, continuum mechanics analysis, in vitro cell culture models, and human clinical data, that heat waves increase risks of cough hypersensitivity, which can be reduced by alkaline aerosols of endogenous salt ions. We predict that the mouth breathing of indoor and outdoor air during heat waves, by exposing human airways to aridity, causes mucosal collapse onto cilia and inflammatory compression of airway epithelial cells. Using airway lining interface cultures of human bronchial epithelial cells, we find that mucosal collapse alters the expression of genes associated with airway hypersensitivity, including TRPV4, PIEZO1, SCNN1A, SCNN1B, ANO1, and CFTR. Our theoretical and experimental models indicate that mucosal collapse can be reversed by inhalation of alkaline (pH\u2009&gt;\u20098) hypertonic divalent salts for 4\u20136 hours by globular protein translocation toward the airway epithelium. We find, on analysis of cough recordings in a recently published clinical trial, that inhaling alkaline hypertonic divalent salt aerosols with pH\u2009&gt;\u20098 every 4\u20136 hours significantly reduced placebo-adjusted cough bouts (34%) (n\u2009=\u20098) (p\u2009=\u20090.01) among refractory chronic cough patients. Inhaled aerosols of the same composition with pH\u2009&lt;\u20098 had no effect on cough bouts (-12%) (n\u2009=\u20094). Aerosols with endogenous ions may help reduce global warming threats to human respiratory health.<\/p>","DOI":"10.21203\/rs.3.rs-6839331\/v1","type":"posted-content","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T11:44:56Z","timestamp":1759751096000},"source":"Crossref","is-referenced-by-count":1,"title":["Heat waves elevate risks of airway hypersensitivity that inhaled endogenous ions reduce"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9313-9551","authenticated-orcid":false,"given":"David","family":"Edwards","sequence":"first","affiliation":[{"name":"JOHNS HOPKINS UNIVERSITY MEDICAL SCHOOL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Button","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelie","family":"Edwards","sequence":"additional","affiliation":[{"name":"Boston University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7101-1426","authenticated-orcid":false,"given":"Kian Fan","family":"Chung","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-4208","authenticated-orcid":false,"given":"Hong","family":"Dang","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Gutay","sequence":"additional","affiliation":[{"name":"University North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Griffin","sequence":"additional","affiliation":[{"name":"University North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Gerenza","sequence":"additional","affiliation":[{"name":"University North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linying","family":"Wang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisham","family":"Abubakar-Waziri","sequence":"additional","affiliation":[{"name":"Imperial College London"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deen","family":"Bhatta","sequence":"additional","affiliation":[{"name":"Sensory Cloud Inc"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Ausiello","sequence":"additional","affiliation":[{"name":"MGH, Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5978-5381","authenticated-orcid":false,"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Boston University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","reference":[{"issue":"8062","key":"ref1","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/s41586-025-08907-1","article-title":"Global emergence of unprecedented lifetime exposure to climate extremes","volume":"641","author":"Grant L","year":"2025","unstructured":"Grant L, Vanderkelen I, Gudmundsson L, Fischer E, Seneviratne SI, Thiery W. Global emergence of unprecedented lifetime exposure to climate extremes. Nature. 2025;641(8062):374\u2013379.","journal-title":"Nature"},{"issue":"168","key":"ref2","doi-asserted-by":"crossref","first-page":"230019","DOI":"10.1183\/16000617.0019-2023","article-title":"Extreme weather and asthma: a systematic review and meta-analysis","volume":"32","author":"Makrufardi F","year":"2023","unstructured":"Makrufardi F, Manullang A, Rusmawatiningtyas D, Chung KF, Lin SC, Chuang HC. Extreme weather and asthma: a systematic review and meta-analysis. Eur Respir Rev. 2023;32(168):230019.","journal-title":"Eur Respir Rev"},{"key":"ref3","first-page":"178087","article-title":"Extreme temperature increases the risk of COPD morbidity and mortality: A systematic review and meta-analysis","volume":"17","author":"Tran HM","year":"2024","unstructured":"Tran HM, Tsai FJ, Lee KY, Wang YH, Yang FM, Ho SC, Bui HTM, Hoang LNN, Bui LTM, Ho KF, Chung KF, Chuang KJ, Chuang HC. Extreme temperature increases the risk of COPD morbidity and mortality: A systematic review and meta-analysis. Sci Total Environ. 17, 178087\u2013110 (2024).","journal-title":"Sci Total Environ."},{"key":"ref4","doi-asserted-by":"crossref","first-page":"594","DOI":"10.3390\/v15030594","article-title":"Association between Temperature and Influenza Activity across Different Regions of China during 2010\u20132017","volume":"15","author":"Wang D","year":"2023","unstructured":"Wang D, Lei H, Wang D, Shu Y, Xiao S. Association between Temperature and Influenza Activity across Different Regions of China during 2010\u20132017. Viruses. 15, 594\u2013612 (2023).","journal-title":"Viruses."},{"issue":"2","key":"ref5","doi-asserted-by":"crossref","first-page":"e16","DOI":"10.5415\/apallergy.2019.9.e16","article-title":"Environmental triggers for chronic cough","volume":"9","author":"Jo EJ","year":"2019","unstructured":"Jo EJ, Song WJ. Environmental triggers for chronic cough. 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The increasing importance of atmospheric demand for ecosystem water and carbon fluxes. Nature Clim Change 6, 1023\u20131027 (2016).","journal-title":"Nature Clim Change"},{"issue":"3","key":"ref12","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1104\/pp.114.252940","article-title":"The evolution of mechanisms driving the stomatal response to vapor pressure deficit","volume":"167","author":"McAdam SA","year":"2015","unstructured":"McAdam SA, Brodribb TJ. The evolution of mechanisms driving the stomatal response to vapor pressure deficit. Plant Physiol. 2015;167(3):833\u201343.","journal-title":"Plant Physiol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1111\/nph.16485","article-title":"Plant responses to rising vapor pressure deficit","volume":"226","author":"Grossiord C","year":"2020","unstructured":"Grossiord C, Buckley TN, Cernusak LA, Novick KA, Poulter B, Siegwolf RTW, Sperry JS, McDowell NG. Plant responses to rising vapor pressure deficit. New Phytol. 226, 1550\u20131566 (2020).","journal-title":"New Phytol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"190123","DOI":"10.1183\/16000617.0123-2019","article-title":"Airway mechanical compression: its role in asthma pathogenesis and progression","volume":"29","author":"Veerati PC","year":"2020","unstructured":"Veerati PC, Mitchel JA, Reid AT, Knight DA, Bartlett NW, Park JA, Grainge CL. Airway mechanical compression: its role in asthma pathogenesis and progression. Eur Respir Rev. 29, 190123\u2013138 (2020).","journal-title":"Eur Respir Rev."},{"key":"ref15","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1146\/annurev-neuro-070918-050509","article-title":"Mechanosensitive Ion Channels: Structural Features Relevant to Mechanotransduction Mechanisms","volume":"43","author":"Jin P","year":"2020","unstructured":"Jin P, Jan LY, Jan YN. Mechanosensitive Ion Channels: Structural Features Relevant to Mechanotransduction Mechanisms. Annu Rev Neurosci. 2020;43:207\u2013229.","journal-title":"Annu Rev Neurosci"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12931-015-0224-4","article-title":"Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells","volume":"16","author":"Nayak PS","year":"2015","unstructured":"Nayak, P.S., Wang, Y., Najrana, T. et al. Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells. 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Shear force sensing of epithelial Na\u2009+\u2009channel (ENaC) relies on N-glycosylated asparagines in the palm and knuckle domains of \u03b1ENaC. Proc Natl Acad Sci U S A. 2020;117(1):717\u2013726.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"ref19","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1002\/jcp.30013","article-title":"Release of ATP by TRPV4 activation is dependent upon the expression of AQP2 in renal cells","volume":"236","author":"Pizzoni A","year":"2021","unstructured":"Pizzoni A, Bazzi Z, Di Giusto G, Alvarez CL, Rivarola V, Capurro C, Schwarzbaum PJ, Ford P. Release of ATP by TRPV4 activation is dependent upon the expression of AQP2 in renal cells. J Cell Physiol. 2021;236(4):2559\u20132571.","journal-title":"J Cell Physiol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"952","DOI":"10.3389\/fphar.2020.00952","article-title":"Hypo-Osmotic Loading Induces Expression of IL-6 in Nucleus Pulposus Cells of the Intervertebral Disc Independent of TRPV4 and TRPM7","volume":"11","author":"Sadowska A","year":"2020","unstructured":"Sadowska A, Altinay B, Hitzl W, Ferguson SJ, Wuertz-Kozak K. Hypo-Osmotic Loading Induces Expression of IL-6 in Nucleus Pulposus Cells of the Intervertebral Disc Independent of TRPV4 and TRPM7. Front Pharmacol. 2020;11:952.","journal-title":"Front Pharmacol"},{"issue":"7772","key":"ref21","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41586-019-1485-8","article-title":"Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity","volume":"573","author":"Solis AG","year":"2019","unstructured":"Solis AG, Bielecki P, Steach HR, Sharma L, Harman CCD, Yun S, de Zoete MR, Warnock JN, To SDF, York AG, Mack M, Schwartz MA, Dela Cruz CS, Palm NW, Jackson R, Flavell RA. Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature. 2019;573(7772):69\u201374.","journal-title":"Nature"},{"issue":"6","key":"ref22","doi-asserted-by":"crossref","first-page":"4120","DOI":"10.1074\/jbc.M311783200","article-title":"Epithelial Na\u2009+\u2009channels are activated by laminar shear stress","volume":"279","author":"Carattino MD","year":"2004","unstructured":"Carattino MD, Sheng S, Kleyman TR. Epithelial Na\u2009+\u2009channels are activated by laminar shear stress. J Biol Chem. 2004;279(6):4120\u20136.","journal-title":"J Biol Chem"},{"issue":"5","key":"ref23","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1161\/HYPERTENSIONAHA.107.093401","article-title":"Sensing tension: epithelial sodium channel\/acid-sensing ion channel proteins in cardiovascular homeostasis","volume":"51","author":"Drummond HA","year":"2008","unstructured":"Drummond HA, Jernigan NL, Grifoni SC. Sensing tension: epithelial sodium channel\/acid-sensing ion channel proteins in cardiovascular homeostasis. Hypertension. 2008;51(5):1265\u201371.","journal-title":"Hypertension"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"1302631","DOI":"10.3389\/fphys.2023.1302631","article-title":"Mechanosensitive channels in lung disease","volume":"14","author":"Zheng M","year":"2023","unstructured":"Zheng M, Borkar NA, Yao Y, Ye X, Vogel ER, Pabelick CM, Prakash YS. Mechanosensitive channels in lung disease. Front Physiol. 2023;14:1302631.","journal-title":"Front Physiol"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1745-9974-7-8","article-title":"Cough response to isocapnic hyperpnoea of dry air and hypertonic saline are interrelated","volume":"7","author":"Purokivi M","year":"2011","unstructured":"Purokivi, M., Koskela, H., Brannan, J.D. et al. Cough response to isocapnic hyperpnoea of dry air and hypertonic saline are interrelated. Cough 7, 8\u201322 (2011).","journal-title":"Cough"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1378\/chest.110.3.632","article-title":"Bronchoconstriction due to cold weather in COPD. The roles of direct airway effects and cutaneous reflex mechanisms","volume":"110","author":"Koskela HO","year":"1996","unstructured":"Koskela HO, Koskela AK, Tukiaineu HO. Bronchoconstriction due to cold weather in COPD. The roles of direct airway effects and cutaneous reflex mechanisms. Chest. 110, 632\u20136 (1996).","journal-title":"Chest"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1152\/physrev.00004.2021","article-title":"Physiology and pathophysiology of human airway mucus","volume":"102","author":"Hill DB","year":"2022","unstructured":"Hill DB, Button B, Rubinstein M, Boucher RC. Physiology and pathophysiology of human airway mucus. Physiol Rev. 102, 1757\u20131836 (2022).","journal-title":"Physiol Rev."},{"key":"ref28","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1477-5956-9-4","article-title":"Analysis of the proteome of human airway epithelial secretions","volume":"9","author":"Ali M","year":"2011","unstructured":"Ali M, Lillehoj EP, Park Y, Kyo Y, Kim KC. Analysis of the proteome of human airway epithelial secretions. Proteome Sci. 2011;9:4.","journal-title":"Proteome Sci"},{"issue":"6","key":"ref29","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1038\/mi.2016.27","article-title":"The innate immune properties of airway mucosal surfaces are regulated by dynamic interactions between mucins and interacting proteins: the mucin interactome","volume":"9","author":"Radicioni G","year":"2016","unstructured":"Radicioni G, Cao R, Carpenter J, Ford AA, Wang T, Li L, Kesimer M. The innate immune properties of airway mucosal surfaces are regulated by dynamic interactions between mucins and interacting proteins: the mucin interactome. Mucosal Immunol. 2016;9(6):1442\u20131454.","journal-title":"Mucosal Immunol"},{"issue":"2","key":"ref30","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1089\/jamp.2011.0914","article-title":"The direct effect of hyperosmolar agents on ciliary beating of human bronchial epithelial cells","volume":"25","author":"Yaghi A","year":"2012","unstructured":"Yaghi A, Zaman A, Dolovich MB. The direct effect of hyperosmolar agents on ciliary beating of human bronchial epithelial cells. J Aerosol Med Pulm Drug Deliv. 2012;25(2): 88\u201395.","journal-title":"J Aerosol Med Pulm Drug Deliv"},{"issue":"9","key":"ref31","first-page":"CD001506","article-title":"Nebulised hypertonic saline for cystic fibrosis","volume":"9","author":"Wark P","year":"2018","unstructured":"Wark P, McDonald VM. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev. 2018;9(9):CD001506.","journal-title":"Cochrane Database Syst Rev"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40635-021-00374-y","article-title":"Rapid changes in mucociliary transport in the tracheal epithelium caused by unconditioned room air or nebulized hypertonic saline and mannitol are not determined by frequency of beating cilia","volume":"17","author":"Kelly SJ","year":"2021","unstructured":"Kelly SJ, Martinsen P, Tatkov S. Rapid changes in mucociliary transport in the tracheal epithelium caused by unconditioned room air or nebulized hypertonic saline and mannitol are not determined by frequency of beating cilia. Intensive Care Med Exp. 17, 8\u201321 (2021).","journal-title":"Intensive Care Med Exp"},{"issue":"3","key":"ref33","doi-asserted-by":"crossref","first-page":"00269","DOI":"10.1183\/23120541.00269-2020","article-title":"Effect of hypertonic saline on mucociliary clearance and clinical outcomes in chronic bronchitis","volume":"6","author":"Bennett WD","year":"2020","unstructured":"Bennett WD, Henderson AG, Ceppe A, Zeman KL, Wu J, Gladman C, Fuller F, Gazda S, Button B, Boucher RC, Donaldson SH. Effect of hypertonic saline on mucociliary clearance and clinical outcomes in chronic bronchitis. ERJ Open Res. 2020;6(3):00269\u20132020.","journal-title":"ERJ Open Res"},{"issue":"5","key":"ref34","doi-asserted-by":"crossref","first-page":"1702652","DOI":"10.1183\/13993003.02652-2017","article-title":"The in vitro effect of nebulised hypertonic saline on human bronchial epithelium","volume":"51","author":"Goralski JL","year":"2018","unstructured":"Goralski JL, Wu D, Thelin WR, Boucher RC, Button B. The in vitro effect of nebulised hypertonic saline on human bronchial epithelium. Eur Respir J. 2018;51(5):1702652","journal-title":"Eur Respir J"},{"key":"ref35","doi-asserted-by":"crossref","DOI":"10.3402\/ecrj.v3.31096","article-title":"'Indirect' challenges from science to clinical practice","author":"Anderson SD","year":"2016","unstructured":"Anderson SD. 'Indirect' challenges from science to clinical practice. Eur Clin Respir J. 2016","journal-title":"Eur Clin Respir J"},{"issue":"3 Pt 1","key":"ref36","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1164\/ajrccm.156.3.9701113","article-title":"A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol","volume":"156","author":"Anderson SD","year":"1997","unstructured":"Anderson SD, Brannan J, Spring J, Spalding N, Rodwell LT, Chan K, Gonda I, Walsh A, Clark AR. A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med. 1997;156(3 Pt 1):758\u201365.","journal-title":"Am J Respir Crit Care Med"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1089\/jamp.2023.0039","article-title":"DA Hypertonic aerosols hydrate airways longer and reduce acidification risk with non-permeating cation and permeating anion salts. Hypertonic Aerosols Hydrate Airways Longer and Reduce Acidification Risk with Nonpermeating Cation and Permeating Anion Salts","volume":"37","author":"Zuim A-F","year":"2024","unstructured":"Zuim, A-F, Edwards, A, Ausiello DA, Bhatta, D Edwards DA Hypertonic aerosols hydrate airways longer and reduce acidification risk with non-permeating cation and permeating anion salts. Hypertonic Aerosols Hydrate Airways Longer and Reduce Acidification Risk with Nonpermeating Cation and Permeating Anion Salts. J Aerosol Med Pulm Drug Deliv. 37, 64\u201376 (2024).","journal-title":"J Aerosol Med Pulm Drug Deliv."},{"issue":"1","key":"ref38","first-page":"L30-41","article-title":"Intracellular calcium oscillations induced by ATP in airway epithelial cells","volume":"277","author":"Evans JH","year":"1999","unstructured":"Evans JH, Sanderson MJ. Intracellular calcium oscillations induced by ATP in airway epithelial cells. Am J Physiol. 1999;277(1):L30-41.","journal-title":"Am J Physiol"},{"issue":"4","key":"ref39","first-page":"1872","article-title":"Down-regulation of cystic fibrosis transmembrane conductance regulator gene expression by agents that modulate intracellular divalent cations","volume":"12","author":"Bargon J","year":"1992","unstructured":"Bargon J, Trapnell BC, Chu CS, Rosenthal ER, Yoshimura K, Guggino WB, Dalemans W, Pavirani A, Lecocq JP, Crystal RG. Down-regulation of cystic fibrosis transmembrane conductance regulator gene expression by agents that modulate intracellular divalent cations. Mol Cell Biol. 1992;12(4):1872\u20138.","journal-title":"Mol Cell Biol"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s12931-019-1077-z","article-title":"Heterogeneity of cough hypersensitivity mediated by TRPV1 and TRPA1 in patients with chronic refractory cough","volume":"20","author":"Long L","year":"2019","unstructured":"Long, L., Yao, H., Tian, J. et al. Heterogeneity of cough hypersensitivity mediated by TRPV1 and TRPA1 in patients with chronic refractory cough. Respir Res 20, 112 (2019).","journal-title":"Respir Res"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00408-023-00664-0","article-title":"Mucus Transpiration as the Basis for Chronic Cough and Cough Hypersensitivity","volume":"20","author":"Edwards DA","year":"2024","unstructured":"Edwards DA, Chung KF. Mucus Transpiration as the Basis for Chronic Cough and Cough Hypersensitivity. Lung. 20, 17\u201324 (2024).","journal-title":"Lung."},{"issue":"9","key":"ref42","doi-asserted-by":"crossref","first-page":"4662","DOI":"10.1021\/acs.jctc.6b00631","article-title":"Evaluation of Methods for the Calculation of the pKa of Cysteine Residues in Proteins","volume":"12","author":"Awoonor-Williams E","year":"2016","unstructured":"Awoonor-Williams E, Rowley CN. Evaluation of Methods for the Calculation of the pKa of Cysteine Residues in Proteins. J Chem Theory Comput. 2016;12(9):4662\u201373.","journal-title":"J Chem Theory Comput"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.jmbbm.2019.06.008","article-title":"Effect of pH on the viscoelastic properties of pig gastric mucus","volume":"98","author":"Parlato RM","year":"2019","unstructured":"Parlato RM, Greco F, Maffettone PL, Larobina D. Effect of pH on the viscoelastic properties of pig gastric mucus. J Mech Behav Biomed Mater. 2019;98:195\u2013199.","journal-title":"J Mech Behav Biomed Mater"},{"key":"ref44","unstructured":"Representative Concentration Pathway (RCP) 8.5 scenario44"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12199-021-00933-5","article-title":"Prevalence of an incompetent lip seal during growth periods throughout Japan: A large-scale, survey-based, cross-sectional study","volume":"26","author":"Nogami Y","year":"2021","unstructured":"Nogami, Y. et al. Prevalence of an incompetent lip seal during growth periods throughout Japan: A large-scale, survey-based, cross-sectional study. Environ. Health Prev. Med. 26, 11 (2021).","journal-title":"Environ. Health Prev. Med."},{"key":"ref46","doi-asserted-by":"crossref","first-page":"3810","DOI":"10.1038\/s41598-024-54328-x","article-title":"Mouth breathing reduces oral function in adolescence","volume":"14","author":"Masutomi Y","year":"2024","unstructured":"Masutomi, Y., Goto, T. & Ichikawa, T. Mouth breathing reduces oral function in adolescence. Sci Rep 14, 3810\u20133825 (2024)","journal-title":"Sci Rep"},{"issue":"2","key":"ref47","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/mi.2012.81","article-title":"Molecular organization of the mucins and glycocalyx underlying mucus transport over mucosal surfaces of the airways","volume":"6","author":"Kesimer M","year":"2013","unstructured":"Kesimer M, Ehre C, Burns KA, Davis CW, Sheehan JK, Pickles RJ. Molecular organization of the mucins and glycocalyx underlying mucus transport over mucosal surfaces of the airways. Mucosal Immunol. 2013;6(2):379\u201392.","journal-title":"Mucosal Immunol"},{"issue":"6","key":"ref48","first-page":"L555-68","article-title":"Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension","volume":"302","author":"Yang XR","year":"2012","unstructured":"Yang XR, Lin AH, Hughes JM, Flavahan NA, Cao YN, Liedtke W, Sham JS. Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2012;302(6):L555-68.","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.thromres.2022.08.006","article-title":"Upregulation of mechanosensitive channel Piezo1 involved in high shear stress-induced pulmonary hypertension","volume":"218","author":"Chen J","year":"2022","unstructured":"Chen J, Miao J, Zhou D, Liao J, Wang Z, Lin Z, Zhang C, Luo X, Li Y, Li X, Liu S, Xing Y, Zhang Z, Zhao M, Parmisano S, Chen Y, Yuan JX, Yang K, Sun D, Wang J. Upregulation of mechanosensitive channel Piezo1 involved in high shear stress-induced pulmonary hypertension. Thromb Res. 2022;218:52\u201363.","journal-title":"Thromb Res"},{"issue":"1","key":"ref50","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1073\/pnas.1911243117","article-title":"Shear force sensing of epithelial Na\u2009+\u2009channel (ENaC) relies on N-glycosylated asparagines in the palm and knuckle domains of \u03b1ENaC","volume":"117","author":"Knoepp F","year":"2020","unstructured":"Knoepp F, Ashley Z, Barth D, Baldin JP, Jennings M, Kazantseva M, Saw EL, Katare R, Alvarez de la Rosa D, Weissmann N, Fronius M. Shear force sensing of epithelial Na\u2009+\u2009channel (ENaC) relies on N-glycosylated asparagines in the palm and knuckle domains of \u03b1ENaC. Proc Natl Acad Sci U S A. 2020;117(1):717\u2013726.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ref51","doi-asserted-by":"crossref","first-page":"e000861","DOI":"10.1136\/bmjresp-2020-000861","article-title":"Downregulation of epithelial sodium channel (ENaC) activity in human airway epithelia after low temperature incubation","volume":"8","author":"Yadav S","year":"2021","unstructured":"Yadav S, Shaughnessy CA, Zeitlin PL, Bratcher PE. Downregulation of epithelial sodium channel (ENaC) activity in human airway epithelia after low temperature incubation. BMJ Open Respir Res. 2021;8(1):e000861.","journal-title":"BMJ Open Respir Res"},{"issue":"4","key":"ref52","first-page":"1872","article-title":"Down-regulation of cystic fibrosis transmembrane conductance regulator gene expression by agents that modulate intracellular divalent cations","volume":"12","author":"Bargon J","year":"1992","unstructured":"Bargon J, Trapnell BC, Chu CS, Rosenthal ER, Yoshimura K, Guggino WB, Dalemans W, Pavirani A, Lecocq JP, Crystal RG. Down-regulation of cystic fibrosis transmembrane conductance regulator gene expression by agents that modulate intracellular divalent cations. Mol Cell Biol. 1992;12(4):1872\u20138.","journal-title":"Mol Cell Biol"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"5844","DOI":"10.1038\/s41467-023-41495-0","article-title":"Chronic cough relief by allosteric modulation of P2X3 without taste disturbance","volume":"14","author":"Guo CR","year":"2023","unstructured":"Guo CR, Zhang ZZ, Zhou X, Sun MY, Li TT, Lei YT, Gao YH, Li QQ, Yue CX, Gao Y, Lin YY, Hao CY, Li CZ, Cao P, Zhu MX, Rong MQ, Wang WH, Yu Y. Chronic cough relief by allosteric modulation of P2X3 without taste disturbance. Nat Commun 14, 5844 (2023).","journal-title":"Nat Commun"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"00241","DOI":"10.1183\/23120541.00241-2024","article-title":"Inhaled alkaline hypertonic divalent salts reduce refractory chronic cough frequency","volume":"10","author":"Abubakar-Waziri H","year":"2024","unstructured":"Abubakar-Waziri H, Edwards DA, Bhatta DB, et al. Inhaled alkaline hypertonic divalent salts reduce refractory chronic cough frequency. ERJ Open Res 2024; 10: 00241\u20132024","journal-title":"ERJ Open Res"},{"issue":"6","key":"ref55","first-page":"00316","article-title":"An exploration of clinically meaningful definitions of cough bouts","volume":"10","author":"Holt KJ","year":"2024","unstructured":"Holt KJ, Dockry RJ, McGuinness K, Barrett E, Smith JA. An exploration of clinically meaningful definitions of cough bouts. ERJ Open Res. 2024;10(6):00316\u20132024.","journal-title":"ERJ Open Res"},{"issue":"5","key":"ref56","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s00408-024-00734-x","article-title":"Longitudinal Cough Frequency Monitoring in Persistent Coughers: Daily Variability and Predictability","volume":"202","author":"Chung KF","year":"2024","unstructured":"Chung KF, Chaccour C, Jover L, Galvosas M, Song WJ, Rudd M, Small P. Longitudinal Cough Frequency Monitoring in Persistent Coughers: Daily Variability and Predictability. Lung. 2024;202(5):561\u2013568.","journal-title":"Lung"},{"issue":"168","key":"ref57","doi-asserted-by":"crossref","first-page":"230019","DOI":"10.1183\/16000617.0019-2023","article-title":"Extreme weather and asthma: a systematic review and meta-analysis","volume":"32","author":"Makrufardi F","year":"2023","unstructured":"Makrufardi F, Manullang A, Rusmawatiningtyas D, Chung KF, Lin SC, Chuang HC. Extreme weather and asthma: a systematic review and meta-analysis. Eur Respir Rev. 2023;32(168):230019.","journal-title":"Eur Respir Rev"},{"issue":"2","key":"ref58","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s00484-013-0655-x","article-title":"The impact of heat waves on children's health: a systematic review","volume":"58","author":"Xu Z","year":"2014","unstructured":"Xu Z, Sheffield PE, Su H, Wang X, Bi Y, Tong S. The impact of heat waves on children's health: a systematic review. Int J Biometeorol. 2014;58(2):239\u201347.","journal-title":"Int J Biometeorol"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"24732","DOI":"10.1038\/s41598-024-75224-4","article-title":"Compound impact of heatwaves on vulnerable groups considering age, income, and disability","volume":"14","author":"Kang Y","year":"2024","unstructured":"Kang, Y., Park, J. & Jang, DH. Compound impact of heatwaves on vulnerable groups considering age, income, and disability. Sci Rep 14, 24732 (2024).","journal-title":"Sci Rep"},{"key":"ref60","first-page":"S2542","article-title":"Community-based heat adaptation interventions for improving heat literacy, behaviours, and health outcomes: a systematic review","volume":"18","author":"Johar H","unstructured":"Johar H, Abdulsalam FI, Guo Y, Baernighausen T, Jahan NK, Watterson J, Leder K, Gouwanda D, Letchuman Ramanathan GR, Lee KKC, Mohamed N, Zakaria TA, Barteit S, Su TT. Community-based heat adaptation interventions for improving heat literacy, behaviours, and health outcomes: a systematic review. Lancet Planet Health. 2025 Apr 18:S2542-5196(25)00007\u2009\u2013\u20095.","journal-title":"Lancet Planet Health. 2025 Apr"},{"issue":"2","key":"ref61","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1074\/jbc.M806954200","article-title":"Extracellular protons regulate human ENaC by modulating Na\u2009+\u2009self-inhibition","volume":"284","author":"Collier DM","year":"2009","unstructured":"Collier DM, Snyder PM. Extracellular protons regulate human ENaC by modulating Na\u2009+\u2009self-inhibition. J Biol Chem. 2009;284(2):792\u20138.","journal-title":"J Biol Chem"},{"issue":"12","key":"ref62","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.3390\/ijms17122090","article-title":"Rat Aquaporin-5 Is pH-Gated Induced by Phosphorylation and Is Implicated in Oxidative Stress","volume":"17","author":"Rodrigues C","year":"2016","unstructured":"Rodrigues C, M\u00f3sca AF, Martins AP, Nobre T, Prista C, Antunes F, Cipak Gasparovic A, Soveral G. Rat Aquaporin-5 Is pH-Gated Induced by Phosphorylation and Is Implicated in Oxidative Stress. Int J Mol Sci. 2016;17(12):2090.","journal-title":"Int J Mol Sci"},{"issue":"Suppl 2","key":"ref63","first-page":"S156-62","article-title":"Mucus Hyperconcentration as a Unifying Aspect of the Chronic Bronchitic Phenotype","volume":"13","author":"Button B","year":"2016","unstructured":"Button B, Anderson WH, Boucher RC. Mucus Hyperconcentration as a Unifying Aspect of the Chronic Bronchitic Phenotype. Ann Am Thorac Soc. 2016;13 Suppl 2(Suppl 2):S156-62.","journal-title":"Ann Am Thorac Soc"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.jmbbm.2019.06.008","article-title":"Effect of pH on the viscoelastic properties of pig gastric mucus","volume":"98","author":"Parlato RM","year":"2019","unstructured":"Parlato RM, Greco F, Maffettone PL, Larobina D. Effect of pH on the viscoelastic properties of pig gastric mucus. 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