Decrease of extracellular volume triggers exercise-induced bronchoconstriction to protect the body from water loss

Decrease of extracellular volume triggers exercise-induced bronchoconstriction to protect the body from water loss | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Decrease of extracellular volume triggers exercise-induced bronchoconstriction to protect the body from water loss Li Yu, Yun Zhou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-305345/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Exercise-Induced Bronchoconstriction describes the narrowing of the airway that occurs during or immediately after exercise. People with Exercise-Induced Bronchoconstriction are very sensitive to both low temperatures and dry air, the physiological mechanism of Exercise-Induced Bronchoconstriction is not very clear. This study aims to investigate the physiological mechanisms of Exercise-Induced Bronchoconstriction in view of the body self-protection response. Methods: The values of the extracellular volume of 23 Exercise-Induced Bronchoconstriction alone compared with the values of 23 healthy adults by comparing the values of their 24-hour urinary sodium excretion, since it is a non-invasive examination. Result: The values of the extracellular volume of the patients were lower than that of healthy adults. Conclusion: We propose that the exercise-induced bronchoconstriction is a kind of an unconditional response that protects the body from water loss, more specifically, the decrease of extracellular volume triggers Exercise-induced bronchoconstriction to protect the body from water loss. Pulmonology Asthma Exercise-induced bronchoconstriction Unconditioned response Urinary sodium excretion Extracellular Volume Figures Figure 1 Figure 2 Introduction Exercise-induced asthma, or more appropriately exercise-induced bronchoconstriction (EIB) describes the narrowing of the airways that occurs during or immediately after exercise ( Ali 2011 ; Caggiano et al. 2017 ; Parsons et al. 2013 ). People who experience EIB are very sensitive to both low temperatures and dry air (Marefati et al. 2015 ; Anderson SD, Kippelen P. 2011 ). EIB usually accompanies chronic asthma (Bonini, Palange 2015 ) and EIB has been in fact reported in 35% to 90% of asthmatic patients ( Weiler et al. 2007 ; Crapo et al.1999 ; McFadden, Gilbert 1994 ; Wuestenfeld , Wolfarth 2013 ). The mechanisms responsible for EIB likely involve multiple mechanistic pathways, here are three popular theories explaining EIB: thermal theories (Chen et al. 1979 ; Gilbert, McFadden 1992 ), airway drying ( Evans et al. 2005 ; Argyros et al. 1993 ), and inflammatory ( Hallstrand et al. 2005 ; Brannan, Turton 2010 ; Anderson, Kippelen 2008 ), but the physiological mechanism of EIB is still not very clear. We think that EIB is mainly caused by the dehydration of the body. In these two coexisted conditions: low extracellular volume (ECV) and relatively dry environment, EIB reduces the expiratory volume ( Hildebrand 2011 ; Hull et al.2016 ), to reduce the loss of water by breathing. This process protects the body from fast and severe dehydration. We think that EIB is an unconditioned response (UCR). Materials And Methods Study design All experimental protocols of this study were approved by Beijing IVY Medical Expert League. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all individual participants included in the study. From the Aldosterone - Urinary sodium excretion (UNaV) curves ( Brunner et al. 1972 ) and the Aldosterone -ECV curves ( Bomback et al.2009 ; Bomback, Klemmer 2009 ), we know the lower the UNaV, the lower the ECV. In healthy volunteers (no kidney disease), a salt load should lead to expansion of ECV and resultant suppression of aldosterone. We could also derive the conclusion from the logical reasoning below: The lower UNaV → means more UNaV were absorbed by the body → means lower Na in the body → means lower ECV to keep sodium concentration above the lowest level for normal metabolism, so lower UNaV means lower ECV. In the study we compare the relative value of the ECV based on the 24h UNaV readings, as the UNaV values are easier to monitor. Subjects Twenty-three subjects aged 23 to 50 years old with physician-diagnosed EIB alone that has no other relevant factors and twenty-three healthy people were recruited, subjects characteristics at baseline are presented in Table 1. Descriptive Statistics Table are presented in Table 2 and Table 3. Subjects who volunteered for the study were currently not taking any diuretics 48h prior to the Urine collection; Caffeine/Tea/alcohol and physical exercise was not permitted 24h respectively prior to the urine collection. All subjects entered the study on their usual diet before the urine collection. Subjects were excluded if they were pregnant, had a history of other chronic disease. Table 1. Characteristics of study participants Variable Age Sex BMI (kg/m2) M (n/%) F (n/%) Case group 35.39±8.17 11(47.8) 12(52.2) 21.00±1.54 Health group 36.13±6.54 11(47.8) 12(52.2) 21.30±1.38 M: Male; F: Female Table 2. Descriptive Statistics of case group N Minimum Maximum Mean Std. Deviation Age 23 23.00 50.00 35.39 8.173 BMI 23 18.80 23.60 21.0000 1.53948 Valid N 23 Table 3. Descriptive Statistics of Health group N Minimum Maximum Mean Std. Deviation Age 23 25.00 50.00 36.13 6.539 BMI 23 18.90 23.20 21.2957 1.38317 Valid N 23 Results The result indicates that the UNaV of case group was lower than the specified healthy group, the lower UNaV meant the lower ECV, and so the value of ECV with EIB was relatively low. Discussion This study has shown that ECV was lower in patients with EIB, it means that EIB is related to the dehydration of the body. A latest research ( Hannah Marshall et al. 2020 ) which has proposed that "in healthy adults: i) mild systemic dehydration induced by exercise or fluid restriction leads to pulmonary function impairment, primarily localized to small airways; and ii) systemic, but not local, rehydration reverses these potentially deleterious alterations." also supported our proposal. From an evolutionary perspective, the organisms get some UCR to adapt to the natural environment and these UCR protect the organisms from injury, such as reaction with skin puncture, coughing, sneezing, shiver, and so on. We think that bronchoconstriction is a kind of UCR. In these two coexisted conditions: low extracellular volume and relatively dry environment, the water loss of the body is reduced by bronchoconstriction, which reduces the exchange of gas, bronchoconstriction reducing the exchange of gas has been proved by hypoxia during an EIB attack, so the bronchoconstriction protecting the body from losing more water. Exercise increases the amount of gas exchange, and may induce sweat, leading to more water loss, so bronchoconstriction will more likely to happen during or after exercising, this being the main reason of EIB. Low ECV may be related to low sodium and high potassium in diet and less water drinking. Several studies ( Bar-Yoseph R, et al ; Abdullaev AA et al . ) supporting our hypothesis gotten from logical reasoning and the necessary experiment have shown that sodium benefits for asthma treatment. The relationship between temperature and the absolute saturation of the water in the air is shown in the psychrometric chart found on the website of the German Insurance Association (Gesamtverband 2016 ). In different temperatures, the differences of the amount of water vapor in a parcel of air can be quite large. For example, a parcel of air that is near saturation may contain 39.6 grams of water per cubic meter of air at 35 °C, but only 3.4 grams of water per cubic meter of air at -5 °C. A typical pair of human lungs contains about 700 million alveoli, producing 70 square meter of surface area ( Roberts et al. 2000 ). Each alveolus is wrapped in a fine mesh of capillaries covering about 70% of its area (Ochs et al. 2003 ) and the surface of alveolus is moist ( Saladin, Kenneth 2007 ). So the gas temperature in the lung is near body temperature (37°C) and the water in the gas is almost saturation. In this situation the moisture content of the gas outside the body is much less than it is in the alveolus, so the more cold and dry it is outside, the more body water is lost by breath, the easier bronchoconstriction will occur, this is why people with EIB are very sensitive to both low temperatures and dry air. Fig2 showed EIB flow process. Cold air will take away heat from body, then the body's skin get goose bumps to decrease heat loss, we think that airway may also shrink to decrease the exchange of air and to decrease the heat lose. This may be another factor that leads to bronchoconstriction. Exercise, nutrition, warmth, and accelerated metabolism will affect this kind of bronchoconstriction. We analyze: The irritant gas which is harmful to the body will be prevented by bronchoconstriction which reduces the exchange of gas, the bronchoconstriction protects the body from getting afflicted, it is also a kind of UCR and this kind of bronchoconstriction is called occupational asthma. Some harmless allergens considered harmful to the body by the immune system will be reduced by bronchoconstriction, which reduces the exchange of gas, it is also a kind of UCR and this kind of bronchoconstriction is called allergic asthma. This is an error state of the body self-protection mechanism, the cause is not clear, but it may be related with environmental factors, food additives, human milk etc. A series of bronchoconstriction causing factors overlap together, and this is more likely to increase the degree of bronchoconstriction and exceed the threshold of asthma. The asthma seems to be caused by one factor, but in fact, several factors contribute to this consequence. For example: A modest allergic factor can making bronchoconstriction but may not induce patients with allergic bronchoconstriction to asthma, however, if patients also have the EIB factor, the risk of EIB will be increased. These modest allergic factors taken individually will increase the degree of bronchoconstriction, but not reaching the threshold causing asthma. When combined together, the EIB factor will accumulate up and exceed the threshold causing asthma. Another example: Exercise increases gas intake. Doing exercise in the irritant or allergic air, bronchoconstriction would occur and it can easily exceed the threshold of asthma and cause an EIB attack. Therefore, the patients that have occupational asthma or allergic asthma are more likely to develop EIB. These different types of asthma are heavily intertwined. If we cure or relieve some types of asthma, other types of asthma can also be reduced. Although we found that low ECV may be the reason of EIB, we cannot give the exact threshold of ECV, since there are other known or unknown factors that cause bronchoconstriction. For example, ECV is different with different BMI ( Bomback, Klemmer 2009 ); factors like this are hard to quantify and prioritize. As we know, about 32-47% of total body sodium is in human bones (Forbes 1960 ), the chronic shortage of sodium in ECV will decrease the sodium in the bones, a part of increased sodium by diets will restore to bones, the process may be slow, and reaching a stable ECV at an appropriate level may need a slow and long process, depending on the patient's specific situation. From UCR view we think EIB is a body self-protection mechanism for the body and asthma falls under the same category. The paper “Is High Blood Pressure Self-Protection for the Brain?” ( Warnert et al. 2016 ) is from the same protection view. There might be some other diseases that can also be explained based on the body self-defense mechanism. Declarations Acknowledgments We wish to thank Liviu Cosacescu MEng , Ying Huang PhD and XingHuaYang PhD, for their advice on this study and thoughtful comments on drafts of this paper. The authors declare no competing financial interests. References Abdullaev AA, Gadzhiev KM, Eiubova AA. The efficacy of speleotherapy in salt mines in children with bronchial asthma based on the data from immediate and late observations. Vopr Kurortol Fizioter Lech Fiz Kult. 1993 Sep-Oct;(5):25-8. View in: PubMed Ali Z. How to diagnose exercise induced asthma? Asian J Sports Med. 2011 Jun;2(2):63-7. PMID: 22375220. View in: PubMed Anderson SD, Kippelen P. Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes. J Allergy Clin Immunol. 2008 Aug;122(2):225-35; quiz 236-7. doi: 10.1016/j.jaci.2008.05.001 . View in: PubMed Anderson SD, Kippelen P. 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Pediatr Pulmonol. 2017 May;52(5):580-587. Epub 2016 Oct 10. doi: 10.1002/ppul.23621 . View in: PubMed Gesamtverband der Deutschen Versicherungswirtschaft e.V. (GDV, German Insurance Association). Climate/humidity table. Dec 03, 2016. Available from http://www.tis-gdv.de/tis_e/misc/klima.htm Gilbert IA, McFadden ER Jr. Airway cooling and rewarming. The second reaction sequence in exercise-induced asthma. J Clin Invest. 1992 Sep; 90(3): 699–704.doi: 10.1172/JCI115940 . View in: PubMed Hildebrand Katarzyna. [Exercise-induced bronchoconstriction]. Pneumonol Alergol Pol. 2011;79(1):39-47 . View in: PubMed Hull JH, Ansley L, Price OJ, Dickinson JW, Bonini M. Eucapnic Voluntary Hyperpnea: Gold Standard for Diagnosing Exercise-Induced Bronchoconstriction in Athletes? Sports Med. 2016; 46: 1083–1093. Published online 2016 Mar 23. doi: 10.1007/s40279-016-0491-3 View in: PubMed Hallstrand TS, Moody MW, Wurfel MM, Schwartz LB, Henderson WR Jr, Aitken ML. Inflammatory basis of exercise-induced bronchoconstriction. Am J Respir Crit Care Med. 2005 Sep 15;172(6):679-86. doi: 10.1164/rccm.200412-1667OC . View in: PubMed Hannah Marshall, , Oliver R. Gibson, Lee M. Romer, Camilla R. Illidi, James H. Hull, and Pascale Kippelen. Systemic but not local rehydration restores dehydration-induced changes in pulmonary function in healthy adults. 10 DEC 2020 doi: 10.1152/japplphysiol.00311.2020 McFadden ER Jr, Gilbert IA.Exercise-induced asthma. N Engl J Med 330: 1362–1367. doi: 10.1056/NEJM199405123301907 . View in: PubMed Marefati H, Vizvari E, Esmaeilizadeh M, Boskabady MH. The effect of climatic conditions on exercise-induced bronchoconstriction in 10–12 year old students. J Bodyw Mov Ther. 2016 Jul;20(3):549-53. doi: 10.1016/j.jbmt.2015.12.007 . View in: PubMed Ochs M1, Nyengaard JR, Jung A, Knudsen L, Voigt M, Wahlers T, Richter J, Gundersen HJ. The number of alveoli in the human lung. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-305345","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":17148579,"identity":"a73dbb63-a1ca-4d36-8c7d-dd35fcb8825e","order_by":0,"name":"Li Yu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYHACxgM8QJKfmbHhwAcGhgSi9IC1SLY3H3w4gyQtBmeOJRvzEKPF4HjvgwNvGA4nNtzIMZO2bbPL42dvYPzwMQePljPHDQ7OAWppnAHUktuWXCzZc4BZcuY23FrMbqQxHOYBammWAGthTtxwI4GNmZcYLW0gLZZt9SRo6eEBep+x7TBhLfZnjjEA/ZJuPIMdGMg9544nzuw52IzXL5LtbYwP3jBYy+4/DIzKH2XVif1AvR8+4tECBoz/mqEMNjDZQEA9GNRB6T/EKB4Fo2AUjIKRBgCzElrO5ezRFgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-0176-3021","institution":"Beijing IVY Medical Expert League","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Yu","suffix":""},{"id":17148580,"identity":"0c3d3918-f5fb-4641-9c02-9f173d999127","order_by":1,"name":"Yun Zhou","email":"","orcid":"","institution":"Beijing Tiantan Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2021-03-06 19:41:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-305345/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-305345/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":7114524,"identity":"ec0e4d9d-3ba4-4124-a9eb-8bdf86a1dd98","added_by":"auto","created_at":"2021-03-18 17:24:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":18387,"visible":true,"origin":"","legend":"Proposed the comparison of the two group ","description":"","filename":"f1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-305345/v1/8e7964ebb775484439cba1e5.jpg"},{"id":7114525,"identity":"1467f6f5-ccf0-49eb-a2d0-1e83ecb4a301","added_by":"auto","created_at":"2021-03-18 17:24:26","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":43588,"visible":true,"origin":"","legend":"EIB flow process. ","description":"","filename":"f2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-305345/v1/dbb608c12bb3c2ddadbaf5e7.jpg"},{"id":13681584,"identity":"e2ae35d6-f6c5-4f36-991a-785cac9bd132","added_by":"auto","created_at":"2021-09-17 11:52:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":247039,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-305345/v1/086ab4a7-cc31-4da3-a122-81306b6d6536.pdf"}],"financialInterests":"","formattedTitle":"Decrease of extracellular volume triggers exercise-induced bronchoconstriction to protect the body from water loss","fulltext":[{"header":"Introduction","content":"\u003cp\u003eExercise-induced asthma, or more appropriately exercise-induced bronchoconstriction (EIB) describes the narrowing of the airways that occurs during or immediately after exercise (\u003ca href=\"#OLE_LINK1\"\u003eAli 2011\u003c/a\u003e;\u003ca href=\"#OLE_LINK2\"\u003e Caggiano et al. 2017\u003c/a\u003e; \u003ca href=\"#OLE_LINK3\"\u003eParsons et al. 2013\u003c/a\u003e). People who experience EIB are very sensitive to both low temperatures and dry air \u003ca href=\"#OLE_LINK4\"\u003e(Marefati et al. 2015\u003c/a\u003e; \u003ca href=\"#OLE_LINK5\"\u003eAnderson SD, Kippelen P. 2011\u003c/a\u003e). EIB usually accompanies chronic asthma \u003ca href=\"#OLE_LINK6\"\u003e(Bonini, Palange 2015\u003c/a\u003e) and EIB has been in fact reported in 35% to 90% of asthmatic patients (\u003ca href=\"#OLE_LINK7\"\u003eWeiler et al. 2007\u003c/a\u003e; \u003ca href=\"#OLE_LINK8\"\u003eCrapo et al.1999\u003c/a\u003e; \u003ca href=\"#OLE_LINK9\"\u003eMcFadden, Gilbert 1994\u003c/a\u003e; \u003ca href=\"#OLE_LINK10\"\u003eWuestenfeld , Wolfarth 2013\u003c/a\u003e).\u003c/p\u003e\n\u003cp\u003eThe mechanisms responsible for EIB likely involve multiple mechanistic pathways, here are three popular theories explaining EIB: thermal theories \u003ca href=\"#OLE_LINK11\"\u003e(Chen et al. 1979\u003c/a\u003e; \u003ca href=\"#OLE_LINK12\"\u003eGilbert, McFadden 1992\u003c/a\u003e), airway drying (\u003ca href=\"#OLE_LINK13\"\u003eEvans et al. 2005\u003c/a\u003e; \u003ca href=\"#OLE_LINK14\"\u003eArgyros et al. 1993\u003c/a\u003e), and inflammatory (\u003ca href=\"#OLE_LINK15\"\u003eHallstrand et al. 2005\u003c/a\u003e; \u003ca href=\"#OLE_LINK16\"\u003eBrannan, Turton 2010\u003c/a\u003e; \u003ca href=\"#OLE_LINK17\"\u003eAnderson, Kippelen 2008\u003c/a\u003e), but the physiological mechanism of EIB is still not very clear.\u003c/p\u003e\n\u003cp\u003eWe think that EIB is mainly caused by the dehydration of the body. In these two coexisted conditions: low extracellular volume (ECV) and relatively dry environment, EIB reduces the expiratory volume (\u003ca href=\"#OLE_LINK18\"\u003eHildebrand 2011\u003c/a\u003e; \u003ca href=\"#OLE_LINK19\"\u003eHull et al.2016\u003c/a\u003e), to reduce the loss of water by breathing. This process protects the body from fast and severe dehydration. We think that EIB is an unconditioned response (UCR).\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e\u003cem\u003eStudy design\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll experimental protocols of this study were approved by Beijing IVY Medical Expert League. All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all individual participants included in the study.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFrom the Aldosterone - Urinary sodium excretion (UNaV) curves (\u003ca href=\"#OLE_LINK20\"\u003eBrunner et al. 1972\u003c/a\u003e) and the Aldosterone -ECV curves (\u003ca href=\"#OLE_LINK21\"\u003eBomback et al.2009\u003c/a\u003e; \u003ca href=\"#OLE_LINK22\"\u003eBomback, Klemmer 2009\u003c/a\u003e), we know the lower the UNaV, the lower the ECV.\u0026nbsp; In healthy volunteers (no kidney disease), a salt load should lead to expansion of ECV and resultant suppression of aldosterone.\u003c/p\u003e\n\u003cp\u003eWe could also derive the conclusion from the logical reasoning below:\u003c/p\u003e\n\u003cp\u003eThe lower UNaV \u0026rarr; means more UNaV were absorbed by the body \u0026rarr; means lower Na in the body \u0026rarr; means lower ECV to keep sodium concentration above the lowest level for normal metabolism, so lower UNaV means lower ECV.\u003c/p\u003e\n\u003cp\u003eIn the study we compare the relative value of the ECV based on the 24h UNaV readings, as the UNaV values are easier to monitor.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSubjects\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-three subjects aged 23 to 50 years old with physician-diagnosed EIB alone that has no other relevant factors and twenty-three healthy people were recruited, subjects characteristics at baseline are presented in Table 1. Descriptive Statistics Table are presented in Table 2 and Table 3. Subjects who volunteered for the study were currently not taking any diuretics 48h prior to the Urine collection; Caffeine/Tea/alcohol and physical exercise was not permitted 24h respectively prior to the urine collection. All subjects entered the study on their usual diet before the urine collection. Subjects were excluded if they were pregnant, had a history of other chronic disease.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"567\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" width=\"567\"\u003e\n\u003cp\u003e\u003cem\u003eTable 1.\u003c/em\u003e\u0026nbsp; Characteristics of study participants\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"134\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"134\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"182\"\u003e\n\u003cp\u003eSex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"118\"\u003e\n\u003cp\u003eBMI (kg/m2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"134\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"134\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003eM (n/%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003eF (n/%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"118\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"134\"\u003e\n\u003cp\u003eCase group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"134\"\u003e\n\u003cp\u003e35.39\u0026plusmn;8.17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e11(47.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e12(52.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"118\"\u003e\n\u003cp\u003e21.00\u0026plusmn;1.54\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"134\"\u003e\n\u003cp\u003eHealth group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"134\"\u003e\n\u003cp\u003e36.13\u0026plusmn;6.54\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e11(47.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e12(52.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"118\"\u003e\n\u003cp\u003e21.30\u0026plusmn;1.38\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"134\"\u003e\n\u003cp\u003eM: Male; F: Female\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"134\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"118\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eTable 2.\u003c/em\u003eDescriptive Statistics of case group\u003c/p\u003e\n\u003ctable border=\"1\" width=\"539\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"112\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"78\"\u003e\n\u003cp\u003eMinimum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003eMaximum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003eMean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"111\"\u003e\n\u003cp\u003eStd. Deviation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"78\"\u003e\n\u003cp\u003e23.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e50.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e35.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"111\"\u003e\n\u003cp\u003e8.173\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eBMI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"78\"\u003e\n\u003cp\u003e18.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e23.60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e21.0000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"111\"\u003e\n\u003cp\u003e1.53948\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eValid N\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"78\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"111\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eTable 3.\u003c/em\u003eDescriptive Statistics of Health group\u003c/p\u003e\n\u003ctable border=\"1\" width=\"539\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"112\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"78\"\u003e\n\u003cp\u003eMinimum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003eMaximum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003eMean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"111\"\u003e\n\u003cp\u003eStd. Deviation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"78\"\u003e\n\u003cp\u003e25.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e50.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e36.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"111\"\u003e\n\u003cp\u003e6.539\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eBMI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"78\"\u003e\n\u003cp\u003e18.90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e23.20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\n\u003cp\u003e21.2957\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"111\"\u003e\n\u003cp\u003e1.38317\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003eValid N\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"78\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"86\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"111\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Results","content":"\u003cp\u003eThe result indicates that the UNaV of case group was lower than the specified healthy group, the lower UNaV meant the lower ECV, and so the value of ECV with EIB was relatively low.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDiscussion\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study has shown that ECV was lower in patients with EIB, it means that EIB is related to the dehydration of the body. A latest research (\u003ca href=\"#OLE_LINK43\"\u003eHannah Marshall et al. 2020\u003c/a\u003e) which has proposed that \"in healthy adults: i) mild systemic dehydration induced by exercise or fluid restriction leads to pulmonary function impairment, primarily localized to small airways; and ii) systemic, but not local, rehydration reverses these potentially deleterious alterations.\" also supported our proposal.\u003c/p\u003e\n\u003cp\u003eFrom an evolutionary perspective, the organisms get some UCR to adapt to the natural environment and these UCR protect the organisms from injury, such as reaction with skin puncture, coughing, sneezing, shiver, and so on. We think that bronchoconstriction is a kind of UCR. In these two coexisted conditions: low extracellular volume and relatively dry environment, the water loss of the body is reduced by bronchoconstriction, which reduces the exchange of gas, bronchoconstriction reducing the exchange of gas has been proved by hypoxia during an EIB attack, so the bronchoconstriction protecting the body from losing more water. Exercise increases the amount of gas exchange, and may induce sweat, leading to more water loss, so bronchoconstriction will more likely to happen during or after exercising, this being the main reason of EIB. Low ECV may be related to low sodium and high potassium in diet and less water drinking. Several studies (\u003ca href=\"#OLE_LINK23\"\u003eBar-Yoseph R, et al\u003c/a\u003e; \u003ca href=\"#OLE_LINK40\"\u003eAbdullaev AA et al\u003c/a\u003e\u003cu\u003e.\u003c/u\u003e) supporting our hypothesis gotten from logical reasoning and the necessary experiment have shown that sodium benefits for asthma treatment.\u003c/p\u003e\n\u003cp\u003eThe relationship between temperature and the absolute saturation of the water in the air is shown in the psychrometric chart found on the website of the German Insurance Association \u003ca href=\"#OLE_LINK24\"\u003e(Gesamtverband 2016\u003c/a\u003e). In different temperatures, the differences of the amount of water vapor in a parcel of air can be quite large. For example, a parcel of air that is near saturation may contain 39.6 grams of water per cubic meter of air at 35 \u0026deg;C, but only 3.4 grams of water per cubic meter of air at -5 \u0026deg;C. A typical pair of human lungs contains about 700 million alveoli, producing 70 square meter of surface area (\u003ca href=\"#OLE_LINK25\"\u003eRoberts et al. 2000\u003c/a\u003e). Each alveolus is wrapped in a fine mesh of capillaries covering about 70% of its area \u003ca href=\"#OLE_LINK26\"\u003e(Ochs et al. 2003\u003c/a\u003e) and the surface of alveolus is moist (\u003ca href=\"#OLE_LINK27\"\u003eSaladin, Kenneth 2007\u003c/a\u003e). So the gas temperature in the lung is near body temperature (37\u0026deg;C) and the water in the gas is almost saturation. In this situation the moisture content of the gas outside the body is much less than it is in the alveolus, so the more cold and dry it is outside, the more body water is lost by breath, the easier bronchoconstriction will occur, this is why people with EIB are very sensitive to both low temperatures and dry air. Fig2 showed EIB flow process.\u003c/p\u003e\n\u003cp\u003eCold air will take away heat from body, then the body's skin get goose bumps to decrease heat loss, we think that airway may also shrink to decrease the exchange of air and to decrease the heat lose. This may be another factor that leads to bronchoconstriction. Exercise, nutrition, warmth, and accelerated metabolism will affect this kind of bronchoconstriction.\u003c/p\u003e\n\u003cp\u003eWe analyze: The irritant gas which is harmful to the body will be prevented by bronchoconstriction which reduces the exchange of gas, the bronchoconstriction protects the body from getting afflicted, it is also a kind of UCR and this kind of bronchoconstriction is called occupational asthma. Some harmless allergens considered harmful to the body by the immune system will be reduced by bronchoconstriction, which reduces the exchange of gas, it is also a kind of UCR and this kind of bronchoconstriction is called allergic asthma. This is an error state of the body self-protection mechanism, the cause is not clear, but it may be related with environmental factors, food additives, human milk etc.\u003c/p\u003e\n\u003cp\u003eA series of bronchoconstriction causing factors overlap together, and this is more likely to increase the degree of bronchoconstriction and exceed the threshold of asthma. The asthma seems to be caused by one factor, but in fact, several factors contribute to this consequence. For example: A modest allergic factor can making bronchoconstriction but may not induce patients with allergic bronchoconstriction to asthma, however, if patients also have the EIB factor, the risk of EIB will be increased.\u003c/p\u003e\n\u003cp\u003eThese modest allergic factors taken individually will increase the degree of bronchoconstriction, but not reaching the threshold causing asthma. When combined together, the EIB factor will accumulate up and exceed the threshold causing asthma.\u0026nbsp; Another example: Exercise increases gas intake. Doing exercise in the irritant or allergic air, bronchoconstriction would occur and it can easily exceed the threshold of asthma and cause an EIB attack. Therefore, the patients that have occupational asthma or allergic asthma are more likely to develop EIB. These different types of asthma are heavily intertwined. If we cure or relieve some types of asthma, other types of asthma can also be reduced.\u003c/p\u003e\n\u003cp\u003eAlthough we found that low ECV may be the reason of EIB, we cannot give the exact threshold of ECV, since there are other known or unknown factors that cause bronchoconstriction. For example, ECV is different with different BMI (\u003ca href=\"#OLE_LINK28\"\u003eBomback, Klemmer 2009\u003c/a\u003e); factors like this are hard to quantify and prioritize. As we know, about 32-47% of total body sodium is in human bones \u003ca href=\"#OLE_LINK29\"\u003e(Forbes 1960\u003c/a\u003e), the chronic shortage of sodium in ECV will decrease the sodium in the bones, a part of increased sodium by diets will restore to bones, the process may be slow, and reaching a stable ECV at an appropriate level may need a slow and long process, depending on the patient's specific situation.\u003c/p\u003e\n\u003cp\u003eFrom UCR view we think EIB is a body self-protection mechanism for the body and asthma falls under the same category. The paper \u0026ldquo;Is High Blood Pressure Self-Protection for the Brain?\u0026rdquo; (\u003ca href=\"#OLE_LINK30\"\u003eWarnert et al. 2016\u003c/a\u003e) is from the same protection view. There might be some other diseases that can also be explained based on the body self-defense mechanism.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eAcknowledgments\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe wish to thank Liviu Cosacescu MEng , Ying Huang PhD and XingHuaYang PhD, for their advice on this study and thoughtful comments on drafts of this paper. The authors declare no competing financial interests.\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003eAbdullaev AA, Gadzhiev KM, Eiubova AA. The efficacy of speleotherapy in salt mines in children with bronchial asthma based on the data from immediate and late observations. Vopr Kurortol Fizioter Lech Fiz Kult. 1993 Sep-Oct;(5):25-8.\u003c/p\u003e\n\u003cp\u003eView in: \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/8266663\"\u003ePubMed\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003eAli Z. How to diagnose exercise induced asthma? Asian J Sports Med. 2011 Jun;2(2):63-7. PMID: 22375220.\u003c/p\u003e\n\u003cp\u003eView in: \u003ca href=\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289196/\"\u003ePubMed\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003eAnderson SD, Kippelen P. Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes. J Allergy Clin Immunol. 2008 Aug;122(2):225-35; quiz 236-7. doi: \u003ca href=\"https://linkinghub.elsevier.com/retrieve/pii/S0091674908007859\"\u003e10.1016/j.jaci.2008.05.001\u003c/a\u003e.\u003c/p\u003e\n\u003cp\u003eView in: \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/18554705/\"\u003ePubMed\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003eAnderson SD, Kippelen P. Assessment and prevention of exercise-induced bronchoconstriction. 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Published online 2016 Mar 23. doi:\u0026nbsp; \u003ca href=\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963444/\"\u003e10.1007/s40279-016-0491-3\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003eView in:\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/27007599\"\u003e PubMed\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003eHallstrand TS, Moody MW, Wurfel MM, Schwartz LB, Henderson WR Jr, Aitken ML. Inflammatory basis of exercise-induced bronchoconstriction. Am J Respir Crit Care Med. 2005 Sep 15;172(6):679-86. doi: \u003ca href=\"https://www.atsjournals.org/doi/full/10.1164/rccm.200412-1667OC\"\u003e10.1164/rccm.200412-1667OC\u003c/a\u003e.\u003c/p\u003e\n\u003cp\u003eView in:\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/15947280\"\u003e PubMed\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003eHannah Marshall, , Oliver R. Gibson, Lee M. Romer, Camilla R. Illidi, James H. Hull, and Pascale Kippelen. 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Epub 2007 Apr 16. doi: \u003ca href=\"https://www.jacionline.org/article/S0091-6749(07)00570-2/fulltext\"\u003e10.1016/j.jaci.2007.02.041\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003eView in: \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=American+Academy+of+Allergy%2C+Asthma+%26+Immunology+Work+Group+Report%3A+Exercise-induced+asthma\"\u003ePubMed\u003c/a\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Asthma, Exercise-induced bronchoconstriction, Unconditioned response, Urinary sodium excretion, Extracellular Volume","lastPublishedDoi":"10.21203/rs.3.rs-305345/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-305345/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003ePurpose:\u003c/em\u003e Exercise-Induced Bronchoconstriction describes the narrowing of the airway that occurs during or immediately after exercise. People with Exercise-Induced Bronchoconstriction are very sensitive to both low temperatures and dry air, the physiological mechanism of Exercise-Induced Bronchoconstriction is not very clear. This study aims to investigate the physiological mechanisms of Exercise-Induced Bronchoconstriction in view of the body self-protection response. \u003cem\u003eMethods:\u003c/em\u003e The values of the extracellular volume of 23 Exercise-Induced Bronchoconstriction alone compared with the values of 23 healthy adults by comparing the values of their 24-hour urinary sodium excretion, since it is a non-invasive examination. \u003cem\u003eResult: \u003c/em\u003eThe values of the extracellular volume of the patients were lower than that of healthy adults. \u003cem\u003eConclusion: \u003c/em\u003eWe propose that the exercise-induced bronchoconstriction is a kind of an unconditional response that protects the body from water loss, more specifically, the decrease of extracellular volume triggers Exercise-induced bronchoconstriction to protect the body from water loss.\u003c/p\u003e","manuscriptTitle":"Decrease of extracellular volume triggers exercise-induced bronchoconstriction to protect the body from water loss","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-18 17:24:23","doi":"10.21203/rs.3.rs-305345/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3ac53e28-b17b-4ce3-908c-bd14607210d1","owner":[],"postedDate":"March 18th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":3063972,"name":"Pulmonology"}],"tags":[],"updatedAt":"2021-03-18T17:24:24+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-18 17:24:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-305345","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-305345","identity":"rs-305345","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}