ssmuБюллетень сибирской медициныBulletin of Siberian Medicine1682-03631819-3684Siberian State Medical University, the Ministry of Healthcare of the Russian Federation10.20538/1682-0363-2021-1-158-167ssmu-4289Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEW AND LECTURESРоль нейротрофических факторов роста в патофизиологии бронхиальной астмы, сочетанной с ожирениемThe role of neurotrophic growth factors in the pathophysiology of bronchial asthma associated with obesityhttps://orcid.org/0000-0001-5018-0271КытиковаО. Ю.KytikovaO. Yu.

 д-р мед. наук, науч. сотрудник, лаборатория восстановительного лечения

 Россия, 690105, г. Владивосток, ул. Русская, 73г 

 73g, Russkaya Str., Vladivostok, 690105, Russian Federation 

kytikova@yandex.ruhttps://orcid.org/0000-0002-6058-201XНовгородцеваТ. П.NovgorodtsevaT. P.

 д-р биол. наук, профессор, гл. науч. сотрудник, лаборатория биомедицинских исследований, зам. директора по научной работе

 Россия, 690105, г. Владивосток, ул. Русская, 73г 

 73g, Russkaya Str., Vladivostok, 690105, Russian Federation 

https://orcid.org/0000-0002-2492-3198АнтонюкМ. В.AntonyukM. V.

 д-р мед. наук, профессор, зав. лабораторией восстановительного лечения

 Россия, 690105, г. Владивосток, ул. Русская, 73г 

 73g, Russkaya Str., Vladivostok, 690105, Russian Federation 

https://orcid.org/0000-0002-6413-9840ГвозденкоТ. А.GvozdenkoT. A.

 д-р мед. наук, профессор РАН, гл. науч. сотрудник, лаборатория восстановительного лечения

 Россия, 690105, г. Владивосток, ул. Русская, 73г 

 73g, Russkaya Str., Vladivostok, 690105, Russian Federation 

Владивостокский филиал «Дальневосточный научный центр физиологии и патологии дыхания» (ДНЦ ФПД) – Научно-исследовательский институт медицинской климатологии и восстановительного лечения (НИИМКИВЛ)РоссияVladivostok branch of the Federal State Government-Funded Science Institution “Far Eastern Scientific Center of Physiology and Pathology of Respiration” – Institute of Medical Climatology and Rehabilitative TreatmentRussian Federation202110042021201158167Copyright © Кытикова О.Ю., Новгородцева Т.П., Антонюк М.В., Гвозденко Т.А., 20212021Кытикова О.Ю., Новгородцева Т.П., Антонюк М.В., Гвозденко Т.А.Kytikova O.Y., Novgorodtseva T.P., Antonyuk M.V., Gvozdenko T.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://bulletin.ssmu.ru/jour/article/view/4289

 Бронхиальная астма (БА) и ожирение являются широко  распространенными заболеваниями с тенденцией к неуклонно прогрессирующему увеличению числа больных.  Сочетанное течение данных заболеваний представляет  собой одну из серьезных проблем современности,  требующих пристального внимания в связи со снижением качества жизни, ухудшением контроля течения основного заболевания, повышением частоты и длительности госпитализации. Если взаимосвязь между БА и ожирением очевидна, то детализация данных механизмов находится в  стадии изучения. В последнее десятилетие в формировании  фенотипа БА, сочетанной с ожирением, пристальное внимание уделяется не только иммунным, но и  нейрогенным механизмам воспалительной реакции.  Известно, что контроль над функционированием всех  отделов нервной системы способны осуществлять нейротрофические факторы роста благодаря их способности влиять на множество механизмов сигнализации. В настоящее время имеются данные об участии  нейротрофических факторов в патогенезе бронхолегочных и метаболических заболеваний. Обзор посвящен  детализации механизма нейрогенного воспаления при  ожирении и БА с участием нейротрофических факторов,  которые могут играть существенную роль в формировании фенотипа БА, сочетанной с ожирением. Изучение новых механизмов, вовлеченных в патогенез БА и ожирения,  позволит найти общие терапевтические мишени для данного фенотипа БА. 

 Bronchial asthma (BA) and obesity are common diseases with a tendency towards a steady and progressive increase in the number of patients. A combination of these diseases is one of the major problems of modern medicine, requiring close attention due to a decrease in the quality of life, poor control over the course of the primary disease, and an increase in the frequency and duration of hospitalization. The association between asthma and obesity is obvious. However, detailed mechanisms underlying it require further investigation. In the last decade, in the formation of the phenotype of BA combined with obesity, much attention has been paid not only to the immune, but also to the neurogenic mechanisms of inflammatory response. It is known that the functioning of all parts of the nervous system can be controlled by neurotrophic growth factors due to their ability to influence many signalling mechanisms. Currently, there is evidence that neurotrophic factors are involved in the pathogenesis of bronchopulmonary and metabolic diseases. The review is devoted to detailed investigation of the mechanisms of neurogenic inflammation in obesity and asthma with participation of neurotrophic factors that may play a significant role in the formation of the BA phenotype associated with obesity. The study of new mechanisms involved in the pathogenesis of asthma and obesity will make it possible to find common therapeutic targets for this asthma phenotype. 

ожирениебронхиальная астманейротрофические факторыobesitybronchial asthmaneurotrophic factorsReferencesGlobal strategy for asthma management and prevention (2016 update). URL: http://ginasthma.org/2016-gina-report-global-strategyfor-asthma-management-and-preventionGlobal strategy for asthma management and prevention (2016 update). URL: http://ginasthma.org/2016-gina-report-global-strategyfor-asthma-management-and-preventionIsrael E., Reddel H.K. Severe and difficult-to-treat asthma in adults. N. Engl. J. Med. 2017; 377 (10): 965–976. DOI: 10.1056/NEJMra1608969.Israel E., Reddel H.K. Severe and difficult-to-treat asthma in adults. N. Engl. J. Med. 2017; 377 (10): 965–976. DOI: 10.1056/NEJMra1608969.Pinnock H., Thomas M., Tsiligianni I., Lisspers K., Østrem A., Ställberg B., Yusuf O., Ryan D., Buffels J., Cals J.W., Chavannes N.H., Henrichsen S.H., Langhammer A., Latysheva E., Lionis C., Litt J., van der Molen T., Zwar N., Williams S. The International primary care respiratory group (IPCRG) research needs statement 2010. Prim. Care Respir. J. 2010; 19 (1): S1–20.Pinnock H., Thomas M., Tsiligianni I., Lisspers K., Østrem A., Ställberg B., Yusuf O., Ryan D., Buffels J., Cals J.W., Chavannes N.H., Henrichsen S.H., Langhammer A., Latysheva E., Lionis C., Litt J., van der Molen T., Zwar N., Williams S. The International primary care respiratory group (IPCRG) research needs statement 2010. Prim. Care Respir. J. 2010; 19 (1): S1–20.Ng M. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014; 384 (9945): 766–781. DOI: 10.1016/S0140-6736(14)60460-8.Ng M. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014; 384 (9945): 766–781. DOI: 10.1016/S0140-6736(14)60460-8.Collaboration NCDRF. Di Cesare M., Bentham J. et al. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet. 2016; 387 (10026): 1377–1396. DOI: 10.1016/S0140-6736(16)30054-X.Collaboration NCDRF. Di Cesare M., Bentham J. et al. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet. 2016; 387 (10026): 1377–1396. DOI: 10.1016/S0140-6736(16)30054-X.Stevens G.A., Singh G.M., Lu Y. et al. National, regional, and global trends in adult overweight and obesity prevalences. Popul. Health Metr. 2012; 10 (1): 22. DOI: 10.1186/1478-7954-10-22.Stevens G.A., Singh G.M., Lu Y. et al. National, regional, and global trends in adult overweight and obesity prevalences. Popul. Health Metr. 2012; 10 (1): 22. DOI: 10.1186/1478-7954-10-22.Popkin B.M., Adair L.S., Ng S.W. Global nutrition transition and the pandemic of obesity in developing countries. Nutr. Rev. 2012; 70 (1): 3–21. DOI: 10.1111/j.1753-4887.2011.00456.x.Popkin B.M., Adair L.S., Ng S.W. Global nutrition transition and the pandemic of obesity in developing countries. Nutr. Rev. 2012; 70 (1): 3–21. DOI: 10.1111/j.1753-4887.2011.00456.x.GBD 2015 Eastern Mediterranean Region Obesity Collaborators. Burden of obesity in the Eastern Mediterranean Region: findings from the global burden of disease 2015 study. Int. J. Public Health. 2018; 63 (1): 165–176. DOI: 10.1007/s00038-017-1002-5.GBD 2015 Eastern Mediterranean Region Obesity Collaborators. Burden of obesity in the Eastern Mediterranean Region: findings from the global burden of disease 2015 study. Int. J. Public Health. 2018; 63 (1): 165–176. DOI: 10.1007/s00038-017-1002-5.Follow-up to the political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases; Geneva. World Health Assembly. 2019. URL: https://apps.who.int/gb/ebwha/pdf_files/WHA72/A72_19-en.pdfFollow-up to the political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases; Geneva. World Health Assembly. 2019. URL: https://apps.who.int/gb/ebwha/pdf_files/WHA72/A72_19-en.pdfClaessen H., Brenner H., Drath C., Arndt V. Repeated measures of body mass index and risk of health related outcomes. Eur. J. Epidemiol. 2012; 27 (3): 215–224. DOI: 10.1007/s10654-012-9669-7.Claessen H., Brenner H., Drath C., Arndt V. Repeated measures of body mass index and risk of health related outcomes. Eur. J. Epidemiol. 2012; 27 (3): 215–224. DOI: 10.1007/s10654-012-9669-7.Kim S.H., Sutherland E., Gelfand E. Is there a link between obesity and asthma? Allergy Asthma Immunol. Res. 2014; 6 (3): 189–195. DOI: 10.4168/aair.2014.6.3.189.Kim S.H., Sutherland E., Gelfand E. Is there a link between obesity and asthma? Allergy Asthma Immunol. Res. 2014; 6 (3): 189–195. DOI: 10.4168/aair.2014.6.3.189.Huang F., Del-Río-Navarro B.E., Torres-Alcántara S., Pérez-Ontiveros J.A., Ruiz-Bedolla E., Saucedo-Ramírez O.J., Villafaña S., Sánchez Muñoz F., Bravo G., Hong E. Adipokines, asymmetrical dimethylarginine, and pulmonary function in adolescents with asthmaand obesity. J. Asthma. 2017; 54 (2): 153–161. DOI: 10.1080/02770903.2016.1200611.Huang F., Del-Río-Navarro B.E., Torres-Alcántara S., Pérez-Ontiveros J.A., Ruiz-Bedolla E., Saucedo-Ramírez O.J., Villafaña S., Sánchez Muñoz F., Bravo G., Hong E. Adipokines, asymmetrical dimethylarginine, and pulmonary function in adolescents with asthmaand obesity. J. Asthma. 2017; 54 (2): 153–161. DOI: 10.1080/02770903.2016.1200611.Santamaria F., Montella S., Greco L., Valerio G., Franzese A., Maniscalco M., Fiorentino G., Peroni D., Pietrobelli A., De Stefano S., Sperlì F., Boner A.L. Obesity duration is associated to pulmonary function impairment in obese subjects. Obesity. 2011; 19 (8): 1623–1628. DOI: 10.1038/oby.2011.1.Santamaria F., Montella S., Greco L., Valerio G., Franzese A., Maniscalco M., Fiorentino G., Peroni D., Pietrobelli A., De Stefano S., Sperlì F., Boner A.L. Obesity duration is associated to pulmonary function impairment in obese subjects. Obesity. 2011; 19 (8): 1623–1628. DOI: 10.1038/oby.2011.1.Shore S.A. Obesity and asthma: possible mechanisms. J. Allergy Clin. Immunol. 2008; 121 (5): 1087–1093. DOI: 10.1016/j.jaci.2008.03.004.Shore S.A. Obesity and asthma: possible mechanisms. J. Allergy Clin. Immunol. 2008; 121 (5): 1087–1093. DOI: 10.1016/j.jaci.2008.03.004.Huh J.Y., Park Y.J., Ham M., Kim J.B. et al. Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol. Cells. 2014; 37 (5): 365–371. DOI: 10.14348/molcells.2014.0074.Huh J.Y., Park Y.J., Ham M., Kim J.B. et al. Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol. Cells. 2014; 37 (5): 365–371. DOI: 10.14348/molcells.2014.0074.Wang М., Wang С., Han R.H., Han Х. Novel advances in shotgun lipidomics for biology and medicine. Prog. Lipid. Res. 2016; 61: 83–108. DOI: 10.1016/j.plipres.2015.12.002.Wang М., Wang С., Han R.H., Han Х. Novel advances in shotgun lipidomics for biology and medicine. Prog. Lipid. Res. 2016; 61: 83–108. DOI: 10.1016/j.plipres.2015.12.002.Barnes P.J. Neurogenic inflammation in the airways. Respir. Physiol. 2001; 125 (1–2): 145–154. DOI: 10.1016/s0034-5687(00)00210-3.Barnes P.J. Neurogenic inflammation in the airways. Respir. Physiol. 2001; 125 (1–2): 145–154. DOI: 10.1016/s0034-5687(00)00210-3.Canning B.J., Woo A., Mazzone S.B. Neuronal modulation of airway and vascular tone and their influence on nonspecific airways responsiveness in asthma. J. Allergy. 2012; 2012: 108149. DOI: 10.1155/2012/108149.Canning B.J., Woo A., Mazzone S.B. Neuronal modulation of airway and vascular tone and their influence on nonspecific airways responsiveness in asthma. J. Allergy. 2012; 2012: 108149. DOI: 10.1155/2012/108149.McAlexander M.A., Gavett S.H., Kollarik M., Undem B.J. Vagotomy reverses established allergen-induced airway hyperreactivity to methacholine in the mouse. Respir. Physiol. Neurobiol. 2015; 212–214: 20–24. DOI: 10.1016/j.resp.2015.03.007.McAlexander M.A., Gavett S.H., Kollarik M., Undem B.J. Vagotomy reverses established allergen-induced airway hyperreactivity to methacholine in the mouse. Respir. Physiol. Neurobiol. 2015; 212–214: 20–24. DOI: 10.1016/j.resp.2015.03.007.Trankner D., Hahne N., Sugino K., Hoon M.A., Zuker C. Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111 (31): 11515–11520. DOI: 10.1073/pnas.1411032111.Trankner D., Hahne N., Sugino K., Hoon M.A., Zuker C. Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111 (31): 11515–11520. DOI: 10.1073/pnas.1411032111.O’Brien Phillipe D., Hinder Lucy M., Callaghan Brian C., Feldman Eva L. Neurological consequences of obesity. Lancet Neurol. 2017; 16 (6): 465–477. DOI: 10.1016/S1474-4422(17)30084-4.O’Brien Phillipe D., Hinder Lucy M., Callaghan Brian C., Feldman Eva L. Neurological consequences of obesity. Lancet Neurol. 2017; 16 (6): 465–477. DOI: 10.1016/S1474-4422(17)30084-4.Nguyen N.L., Randall J., Banfield B.W., Bartness T.J. Central sympathetic innervations to visceral and subcutaneous white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014; 306 (6): R375–386. DOI: 10.1152/ajpregu.00552.2013.Nguyen N.L., Randall J., Banfield B.W., Bartness T.J. Central sympathetic innervations to visceral and subcutaneous white adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014; 306 (6): R375–386. DOI: 10.1152/ajpregu.00552.2013.Zeng W., Pirzgalska R.M., Pereira M.M., Kubasova N., Barateiro A., Seixas E., Lu Y.H., Kozlova A., Voss H., Martins G.G. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell. 2015; 163 (1): 84–94. DOI: 10.1016/j.cell.2015.08.055.Zeng W., Pirzgalska R.M., Pereira M.M., Kubasova N., Barateiro A., Seixas E., Lu Y.H., Kozlova A., Voss H., Martins G.G. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell. 2015; 163 (1): 84–94. DOI: 10.1016/j.cell.2015.08.055.Bays H.E., Toth P.P., Kris-Etherton P.M., Abate N., Aronne L., Brown W.V., Gonzalez-Campoy M., Jones S., Kumar R., La Forge R., Samuel V.O. Obesity, adiposity, and dyslipidemia: a consensus statement from the national lipid association. Journal of Clinical Lipidology. 2013; 7 (4): 304–383. DOI: 10.1016/j.jacl.2013.04.001.Bays H.E., Toth P.P., Kris-Etherton P.M., Abate N., Aronne L., Brown W.V., Gonzalez-Campoy M., Jones S., Kumar R., La Forge R., Samuel V.O. Obesity, adiposity, and dyslipidemia: a consensus statement from the national lipid association. Journal of Clinical Lipidology. 2013; 7 (4): 304–383. DOI: 10.1016/j.jacl.2013.04.001.Guariguata L., Whiting D., Weil C., Unwin N. The International Diabetes Federation diabetes atlas methodology for estimating global and national prevalence of diabetes in adults. Diabetes Res. Clin. Pract. 2011; 94 (3): 322–332. DOI: 10.1016/j.diabres.2011.10.040.Guariguata L., Whiting D., Weil C., Unwin N. The International Diabetes Federation diabetes atlas methodology for estimating global and national prevalence of diabetes in adults. Diabetes Res. Clin. Pract. 2011; 94 (3): 322–332. DOI: 10.1016/j.diabres.2011.10.040.Samson S.L., Garber A.J. Metabolic syndrome. Endocrinol. Metab. Clin. North Am. 2014; 43 (1): 1–23. DOI: 10.1016/j.ecl.2013.09.009.Samson S.L., Garber A.J. Metabolic syndrome. Endocrinol. Metab. Clin. North Am. 2014; 43 (1): 1–23. DOI: 10.1016/j.ecl.2013.09.009.Callaghan B.C., Xia R., Reynolds E., Banerjee M., Burant C., Rothberg A., Pop-Busui R., Villegas-Umana E., Feldman E.L. Better diagnostic accuracy of neuropathy in obesity: A new challenge for neurologists. Clin. Neurophysiol. 2018; 129 (3): 654–662. DOI: 10.1016/j.clinph.2018.01.003.Callaghan B.C., Xia R., Reynolds E., Banerjee M., Burant C., Rothberg A., Pop-Busui R., Villegas-Umana E., Feldman E.L. Better diagnostic accuracy of neuropathy in obesity: A new challenge for neurologists. Clin. Neurophysiol. 2018; 129 (3): 654–662. DOI: 10.1016/j.clinph.2018.01.003.Vincent A.M., Callaghan B.C., Smith A.L., Feldman E.L. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat. Rev. Neurol. 2011; 7 (10): 573–583. DOI: 10.1038/nrneurol.2011.137.Vincent A.M., Callaghan B.C., Smith A.L., Feldman E.L. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat. Rev. Neurol. 2011; 7 (10): 573–583. DOI: 10.1038/nrneurol.2011.137.Mathis D., Shoelson S.E. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 2011; 11 (2): 81. DOI: 10.1038/nri2922.Mathis D., Shoelson S.E. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 2011; 11 (2): 81. DOI: 10.1038/nri2922.Pistell P.J., Morrison C.D., Gupta S., Knight A.G., Keller J.N., Ingram D.K. et al. Cognitive impairment following high fat diet consumption is associated with brain inflammation.Pistell P.J., Morrison C.D., Gupta S., Knight A.G., Keller J.N., Ingram D.K. et al. Cognitive impairment following high fat diet consumption is associated with brain inflammation.J. Neuroimmunol. 2010; 219 (1–2): 25–32. DOI: 10.1016/j.jneuroim.2009.11.010.J. Neuroimmunol. 2010; 219 (1–2): 25–32. DOI: 10.1016/j.jneuroim.2009.11.010.Thaler J.P., Yi C.X., Schur E.A., Guyenet S.J., Hwang B.H., Dietrich M.O. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 2012; 122 (1): 153–162. DOI: 10.1172/JCI59660.Thaler J.P., Yi C.X., Schur E.A., Guyenet S.J., Hwang B.H., Dietrich M.O. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 2012; 122 (1): 153–162. DOI: 10.1172/JCI59660.Gautron L., Elmquist J.K., Williams K.W. Neural control of energy balance: translating circuits to therapies. Cell. 2015; 161 (1): 133–145. DOI: 10.1016/j.cell.2015.02.023.Gautron L., Elmquist J.K., Williams K.W. Neural control of energy balance: translating circuits to therapies. Cell. 2015; 161 (1): 133–145. DOI: 10.1016/j.cell.2015.02.023.Myers M.G.Jr., Olson D.P. Central nervous system control of metabolism. Nature. 2012; 491 (7424): 357–363. DOI: 10.1038/nature11705.Myers M.G.Jr., Olson D.P. Central nervous system control of metabolism. Nature. 2012; 491 (7424): 357–363. DOI: 10.1038/nature11705.Hur J., Dauch J.R., Hinder L.M. et al. The metabolic syndrome and microvascular complications in a murine model of type 2 diabetes. Diabetes. 2015; 64 (9): 3294–3304. DOI: 10.2337/db15-0133.Hur J., Dauch J.R., Hinder L.M. et al. The metabolic syndrome and microvascular complications in a murine model of type 2 diabetes. Diabetes. 2015; 64 (9): 3294–3304. DOI: 10.2337/db15-0133.Aravamudan B., Thompson M., Pabelick C., Prakash Y.S. Brain-derived neurotrophic factor induces proliferation of human airway smooth muscle cells. J. Cell Mol. Med. 2012; 16 (4): 812–823. DOI: 10.1111/j.1582-4934.2011.01356.x.Aravamudan B., Thompson M., Pabelick C., Prakash Y.S. Brain-derived neurotrophic factor induces proliferation of human airway smooth muscle cells. J. Cell Mol. Med. 2012; 16 (4): 812–823. DOI: 10.1111/j.1582-4934.2011.01356.x.Prakash Y.S., Thompson M.A., Meuchel L. Neurotrophins in lung health and disease. Expert Rev. Respir. Med. 2010; 4 (3): 395–411. DOI: 10.1586/ers.10.29.Prakash Y.S., Thompson M.A., Meuchel L. Neurotrophins in lung health and disease. Expert Rev. Respir. Med. 2010; 4 (3): 395–411. DOI: 10.1586/ers.10.29.Barrios J., Ai X. Neurotrophins in asthma. Curr. Allergy Asthma Rep. 2018; 18 (2): 10. DOI: 10.1007/s11882-018-765-y.Barrios J., Ai X. Neurotrophins in asthma. Curr. Allergy Asthma Rep. 2018; 18 (2): 10. DOI: 10.1007/s11882-018-765-y.Chaldakov G. The metabotrophic NGF and BDNF: an emerging concept. Arch. Ital. Biol. 2011; 149 (2): 257–263.Chaldakov G. The metabotrophic NGF and BDNF: an emerging concept. Arch. Ital. Biol. 2011; 149 (2): 257–263.Voutilainen M.H., Arumae U., Airavaara M., Saarma M. Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson’s disease. FEBS Lett. 2015; 589: 3739–3748. DOI: 10.4449/aib.v149i2.1366.Voutilainen M.H., Arumae U., Airavaara M., Saarma M. Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson’s disease. FEBS Lett. 2015; 589: 3739–3748. DOI: 10.4449/aib.v149i2.1366.Aravamudan B., Thompson M.A., Pabelick C.M., Prakash Y.S. Mechanisms of BDNF regulation in asthmatic airway smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 2016; 311 (2): L270–279. DOI: 10.1152/ajplung.00414.2015.Aravamudan B., Thompson M.A., Pabelick C.M., Prakash Y.S. Mechanisms of BDNF regulation in asthmatic airway smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 2016; 311 (2): L270–279. DOI: 10.1152/ajplung.00414.2015.Vohra P.K., Thompson M.A., Sathish V., Kiel A., Jerde C., Pabelick C.M., Singh B.B., Prakash Y.S. TRPC3 regulates release of brain-derived neurotrophic factor from human airway smooth muscle. Biochim. Biophys. Acta. 2013; 1833 (2): 2953–2960. DOI: 10.1016/j.bbamcr.2013.07.019.Vohra P.K., Thompson M.A., Sathish V., Kiel A., Jerde C., Pabelick C.M., Singh B.B., Prakash Y.S. TRPC3 regulates release of brain-derived neurotrophic factor from human airway smooth muscle. Biochim. Biophys. Acta. 2013; 1833 (2): 2953–2960. DOI: 10.1016/j.bbamcr.2013.07.019.Barrios J., Patel K.R., Aven L., Achey R., Minns M.S., Lee Y. et al. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. FASEB J. 2017; 31 (9): 4117– 428. DOI: 10.1096/fj.201700115R.Barrios J., Patel K.R., Aven L., Achey R., Minns M.S., Lee Y. et al. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. FASEB J. 2017; 31 (9): 4117– 428. DOI: 10.1096/fj.201700115R.Sathish V., Vanoosten S.K., Miller B.S., Aravamudan B., Thompson M.A., Pabelick C.M., Vassallo R., Prakash Y.S. Brain-derived neurotrophic factor in cigarette smoke-induced airway hyperreactivity. Am. J. Respir. Cell Mol. Biol. 2013; 48 (4): 431–438. DOI: 10.1165/rcmb.2012-0129OC.Sathish V., Vanoosten S.K., Miller B.S., Aravamudan B., Thompson M.A., Pabelick C.M., Vassallo R., Prakash Y.S. Brain-derived neurotrophic factor in cigarette smoke-induced airway hyperreactivity. Am. J. Respir. Cell Mol. Biol. 2013; 48 (4): 431–438. DOI: 10.1165/rcmb.2012-0129OC.Andiappan A.K., Parate P.N., Anantharaman R., Suri B.K., Wang de Y., Chew F.T. Genetic variation in BDNF is associated with allergic asthma and allergic rhinitis in an ethnic Chinese population in Singapore. Cytokine. 2011; 56 (2): 218–223. DOI: 10.1016/j.cyto.2011.05.008.Andiappan A.K., Parate P.N., Anantharaman R., Suri B.K., Wang de Y., Chew F.T. Genetic variation in BDNF is associated with allergic asthma and allergic rhinitis in an ethnic Chinese population in Singapore. Cytokine. 2011; 56 (2): 218–223. DOI: 10.1016/j.cyto.2011.05.008.Watanabe T., Fajt M.L., Trudeau J.B., Voraphani N., Hu H., Zhou X. et al. Brain-derived neurotrophic factor expression in asthma. Association with severity and type 2 inflammatory processes. Am. J. Respir. Cell Mol. Biol. 2015; 53 (6): 844–852. DOI: 10.1165/rcmb.2015-0015OC.Watanabe T., Fajt M.L., Trudeau J.B., Voraphani N., Hu H., Zhou X. et al. Brain-derived neurotrophic factor expression in asthma. Association with severity and type 2 inflammatory processes. Am. J. Respir. Cell Mol. Biol. 2015; 53 (6): 844–852. DOI: 10.1165/rcmb.2015-0015OC.Singh R.B., Takahashi T., Tokunaga M., Wilczynska A., Kim C.J., Meester F.D., Handjieva-Darlenska T., Cheema S.K., Wilson D.W., Milovanovic B. et al. Effect of brain derived neurotrophic factor, in relation to diet and lifestyle factors, for prevention of neuropsychiatric and vascular diseases and diabetes. Open Nutr. J. 2014; 7: 5–14. DOI: 10.2174/1876396001407010005.Singh R.B., Takahashi T., Tokunaga M., Wilczynska A., Kim C.J., Meester F.D., Handjieva-Darlenska T., Cheema S.K., Wilson D.W., Milovanovic B. et al. Effect of brain derived neurotrophic factor, in relation to diet and lifestyle factors, for prevention of neuropsychiatric and vascular diseases and diabetes. Open Nutr. J. 2014; 7: 5–14. DOI: 10.2174/1876396001407010005.Fonseca-Portilla R., Krell-Roesch J., Shaibi G.Q., Caselli R.J. brain-derived neurotrophic factor and its associations with metabolism and physical activity in a latino sample. Metab. Syndr. Relat. Disord. 2019; 17 (2): 75–80. DOI: 10.1089/met.2018.0028.Fonseca-Portilla R., Krell-Roesch J., Shaibi G.Q., Caselli R.J. brain-derived neurotrophic factor and its associations with metabolism and physical activity in a latino sample. Metab. Syndr. Relat. Disord. 2019; 17 (2): 75–80. DOI: 10.1089/met.2018.0028.Jiménez-Maldonado A., Virgen-Ortiz A., Melnikov V., et al. Effect of moderate and high intensity chronic exercise on the pancreatic islet morphometry in healthy rats: BDNF receptor participation. Islets. 2017; 9 (1): 1–10. DOI: 10.1080/19382014.2016.1260796.Jiménez-Maldonado A., Virgen-Ortiz A., Melnikov V., et al. Effect of moderate and high intensity chronic exercise on the pancreatic islet morphometry in healthy rats: BDNF receptor participation. Islets. 2017; 9 (1): 1–10. DOI: 10.1080/19382014.2016.1260796.Ozek C., Zimmer D.J., de Jonghe B.C., Kalb R.G., Bence K.K. Ablation of intact hypothalamic and/or hindbrain TrkB signaling leads to perturbations in energy balance. Molecular. Metabolism. 2015; 4 (11): 867–880. DOI: 10.1016/j.molmet.2015.08.002.Ozek C., Zimmer D.J., de Jonghe B.C., Kalb R.G., Bence K.K. Ablation of intact hypothalamic and/or hindbrain TrkB signaling leads to perturbations in energy balance. Molecular. Metabolism. 2015; 4 (11): 867–880. DOI: 10.1016/j.molmet.2015.08.002.Roth C.L., Elfers C., Gebhardt U., Müller H. L., Reinehr T. Brain-derived neurotrophic factor and its relation to leptin in obese children before and after weight loss. Metabolism. 2013; 62 (2): 226–234. DOI: 10.1016/j.metabol.2012.08.001.Roth C.L., Elfers C., Gebhardt U., Müller H. L., Reinehr T. Brain-derived neurotrophic factor and its relation to leptin in obese children before and after weight loss. Metabolism. 2013; 62 (2): 226–234. DOI: 10.1016/j.metabol.2012.08.001.Sandrini L., Di Minno A., Amadio P., Ieraci A., Tremoli E., Barbieri S.S. Association between obesity and circulating brain-derived neurotrophic factor (bdnf) levels: systematic review of literature and meta-analysis. Int. J. Mol. Sci. 2018; 19 (8): е2281. DOI: 10.3390/ijms19082281.Sandrini L., Di Minno A., Amadio P., Ieraci A., Tremoli E., Barbieri S.S. Association between obesity and circulating brain-derived neurotrophic factor (bdnf) levels: systematic review of literature and meta-analysis. Int. J. Mol. Sci. 2018; 19 (8): е2281. DOI: 10.3390/ijms19082281.Briana D.D., Malamitsi-Puchner A. Developmental origins of adult health and disease: The metabolic role of BDNF fromBriana D.D., Malamitsi-Puchner A. Developmental origins of adult health and disease: The metabolic role of BDNF fromearly life to adulthood. Metabolism. 2018; 81: 45–51. DOI: 10.1016/j.metabol.2017.11.019.early life to adulthood. Metabolism. 2018; 81: 45–51. DOI: 10.1016/j.metabol.2017.11.019.Walsh J.J., Tschakovsky M.E. Exercise and circulating BDNF: mechanisms of release and implications for the design of exercise interventions. Applied Physiology, Nutrition, and Metabolism. 2018; 43 (11): 1095–1104. DOI: 10.1139/apnm-2018-0192.Walsh J.J., Tschakovsky M.E. Exercise and circulating BDNF: mechanisms of release and implications for the design of exercise interventions. Applied Physiology, Nutrition, and Metabolism. 2018; 43 (11): 1095–1104. DOI: 10.1139/apnm-2018-0192.Szczepankiewicz A., Rachel M., Sobkowiak P., Kycler Z., Wojsyk-Banaszak I., Schoneich N. et al. Neurotrophin serum concentrations and polymorphisms of neurotrophins and their receptors in children with asthma. Respir. Med. 2013; 107 (1): 30–36. DOI: 10.1016/j.rmed.2012.09.024.Szczepankiewicz A., Rachel M., Sobkowiak P., Kycler Z., Wojsyk-Banaszak I., Schoneich N. et al. Neurotrophin serum concentrations and polymorphisms of neurotrophins and their receptors in children with asthma. Respir. Med. 2013; 107 (1): 30–36. DOI: 10.1016/j.rmed.2012.09.024.Pan J., Rhode H.K., Undem B.J., Myers A.C. Neurotransmitters in airway parasympathetic neurons altered by neurotrophin-3 and repeated allergen challenge. Am. J. Respir. Cell Mol. Biol. 2010; 43 (4): 452–457. DOI: 10.1165/rcmb.2009-0130OC.Pan J., Rhode H.K., Undem B.J., Myers A.C. Neurotransmitters in airway parasympathetic neurons altered by neurotrophin-3 and repeated allergen challenge. Am. J. Respir. Cell Mol. Biol. 2010; 43 (4): 452–457. DOI: 10.1165/rcmb.2009-0130OC.Levi-Montalcini R. The nerve growth factor: 35 years later. Science. 1987; 237 (4819): 1154–1162. DOI: 10.1126/science.3306916.Levi-Montalcini R. The nerve growth factor: 35 years later. Science. 1987; 237 (4819): 1154–1162. DOI: 10.1126/science.3306916.Lam N.T., Currie P.D., Lieschke G.J., Rosenthal N.A., Kaye D.M. Nerve growth factor stimulates cardiac regeneration via cardiomyocyte proliferation in experimental heart failure. PLoS One. 2012; 7 (12): e53210. DOI: 10.1371/journal.pone.0053210.Lam N.T., Currie P.D., Lieschke G.J., Rosenthal N.A., Kaye D.M. Nerve growth factor stimulates cardiac regeneration via cardiomyocyte proliferation in experimental heart failure. PLoS One. 2012; 7 (12): e53210. DOI: 10.1371/journal.pone.0053210.Wu Z.X., Hunter D.D., Batchelor T.P., Dey R.D. Side-stream tobacco smoke-induced airway hyperresponsiveness in early postnatal period is involved nerve growth factor. Respir. Physiol. Neurobiol. 2016; 223: 1–8. DOI: 10.1016/j.resp.2015.11.009.Wu Z.X., Hunter D.D., Batchelor T.P., Dey R.D. Side-stream tobacco smoke-induced airway hyperresponsiveness in early postnatal period is involved nerve growth factor. Respir. Physiol. Neurobiol. 2016; 223: 1–8. DOI: 10.1016/j.resp.2015.11.009.Renz H., Kiliç A. Neurotrophins in chronic allergic airway inflammation and remodeling. Chem. Immunol. Allergy. 2012; 98: 100–117. DOI: 10.1159/000336504.Renz H., Kiliç A. Neurotrophins in chronic allergic airway inflammation and remodeling. Chem. Immunol. Allergy. 2012; 98: 100–117. DOI: 10.1159/000336504.Kim J.S., Kang J.Y., Ha J.H., Lee H.Y., Kim S.J., Kim S.C., Ahn J.H., Kwon S.S., Kim Y.K., Lee S.Y. Expression of nerve growth factor and matrix metallopeptidase-9/tissue inhibitor of metalloproteinase-1 in asthmatic patients. J. Asthma. 2013; 50 (7): 712–717. DOI: 10.3109/02770903.2013.808664.Kim J.S., Kang J.Y., Ha J.H., Lee H.Y., Kim S.J., Kim S.C., Ahn J.H., Kwon S.S., Kim Y.K., Lee S.Y. Expression of nerve growth factor and matrix metallopeptidase-9/tissue inhibitor of metalloproteinase-1 in asthmatic patients. J. Asthma. 2013; 50 (7): 712–717. DOI: 10.3109/02770903.2013.808664.Bradding P., Arthur G. Mast cells in asthma-state of the art. Clin. Exp. Allergy. 2016. 46 (2): 194–263. DOI: 10.1111/cea.12675.Bradding P., Arthur G. Mast cells in asthma-state of the art. Clin. Exp. Allergy. 2016. 46 (2): 194–263. DOI: 10.1111/cea.12675.Yang Y.G., Tian W.M., Zhang H., Li M., Shang Y.X. Nerve growth factor exacerbates allergic lung inflammation and airway remodeling in a rat model of chronic asthma. Exp. Ther. Med. 2013; 6 (5): 1251–1258. DOI: 10.3892/etm.2013.1284.Yang Y.G., Tian W.M., Zhang H., Li M., Shang Y.X. Nerve growth factor exacerbates allergic lung inflammation and airway remodeling in a rat model of chronic asthma. Exp. Ther. Med. 2013; 6 (5): 1251–1258. DOI: 10.3892/etm.2013.1284.Nurwidya F., Andarini S., Takahashi F., Syahruddin E., Takahashi K. Implications of insulin-like growth factor 1 receptor activation in lung cancer. Malaysian Journal of Medical Sciences. 2016; 23 (3): 9–21.Nurwidya F., Andarini S., Takahashi F., Syahruddin E., Takahashi K. Implications of insulin-like growth factor 1 receptor activation in lung cancer. Malaysian Journal of Medical Sciences. 2016; 23 (3): 9–21.Trueba-Saiz A., Fernandez A. M., Nishijima T. et al. Circulating insulin-like growth factor i regulates its receptor in the brain of male mice. Endocrinology. 2017; 158 (2): 349–355. DOI: 10.1210/en.2016.1468.Trueba-Saiz A., Fernandez A. M., Nishijima T. et al. Circulating insulin-like growth factor i regulates its receptor in the brain of male mice. Endocrinology. 2017; 158 (2): 349–355. DOI: 10.1210/en.2016.1468.Lee H., Kim S.R., Oh Y., Cho S.H., Schleimer R.P., Lee Y.C. Targeting insulin-like growth factor-I and insulin-like growth factor-binding protein-3 signaling pathways: A novel therapeutic approach for asthma. American Journal of Respiratory Cell and Molecular Biology. 2014; 50 (4): 667– 677. DOI: 10.1165/rcmb.2013-0397TR.Lee H., Kim S.R., Oh Y., Cho S.H., Schleimer R.P., Lee Y.C. Targeting insulin-like growth factor-I and insulin-like growth factor-binding protein-3 signaling pathways: A novel therapeutic approach for asthma. American Journal of Respiratory Cell and Molecular Biology. 2014; 50 (4): 667– 677. DOI: 10.1165/rcmb.2013-0397TR.Frystyk J., Schou A. J., Heuck C., et al. Prednisolone reduces the ability of serum to activate the IGF1 receptor in vitro without affecting circulating total or free IGF1. European Journal of Endocrinology. 2013; 168 (1): 1–8. DOI: 10.1530/EJE-12-0518.Frystyk J., Schou A. J., Heuck C., et al. Prednisolone reduces the ability of serum to activate the IGF1 receptor in vitro without affecting circulating total or free IGF1. European Journal of Endocrinology. 2013; 168 (1): 1–8. DOI: 10.1530/EJE-12-0518.Gobbato N.B., De Souza F.C.R., Fumagalli S.B.N. et al. Antileukotriene reverts the early effects of inflammatory response of distal parenchyma in experimental chronic allergic inflammation. BioMed Research International. 2013; 2013: 523761. DOI: 10.1155/2013/523761.523761.Gobbato N.B., De Souza F.C.R., Fumagalli S.B.N. et al. Antileukotriene reverts the early effects of inflammatory response of distal parenchyma in experimental chronic allergic inflammation. BioMed Research International. 2013; 2013: 523761. DOI: 10.1155/2013/523761.523761.Yao X., Wang W., Li Y. et al. IL-25 induces airways angiogenesis and expression of multiple angiogenic factors in a murine asthma model. Respiratory Research. 2015; 16 (1): 39. DOI: 10.1186/s12931-015-0197-3.Yao X., Wang W., Li Y. et al. IL-25 induces airways angiogenesis and expression of multiple angiogenic factors in a murine asthma model. Respiratory Research. 2015; 16 (1): 39. DOI: 10.1186/s12931-015-0197-3.Kim S.R., Lee K.S., Lee K.B., Lee Y.C. Recombinant IGFBP-3 inhibits allergic lung inflammation, VEGF production, and vascular leak in a mouse model of asthma. Allergy: European Journal of Allergy and Clinical Immunology. 2012; 67 (7): 869–877. DOI: 10.1111/j.1398-9995.2012.02837.x.Kim S.R., Lee K.S., Lee K.B., Lee Y.C. Recombinant IGFBP-3 inhibits allergic lung inflammation, VEGF production, and vascular leak in a mouse model of asthma. Allergy: European Journal of Allergy and Clinical Immunology. 2012; 67 (7): 869–877. DOI: 10.1111/j.1398-9995.2012.02837.x.Han C.Z., Juncadella I.J., Kinchen J.M. et al. Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature. 2016; 539 (7630): 570–574. DOI: 10.1038/nature20141.Han C.Z., Juncadella I.J., Kinchen J.M. et al. Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature. 2016; 539 (7630): 570–574. DOI: 10.1038/nature20141.Haywood N.J., Slater T.A., Matthews C.J., Wheatcroft S.B. The insulin like growth factor and binding protein family:Haywood N.J., Slater T.A., Matthews C.J., Wheatcroft S.B. The insulin like growth factor and binding protein family:Novel therapeutic targets in obesity & diabetes. Mol. Metab. 2019: 19: 86–96. DOI: 10.1016/j.molmet.2018.10.008.Novel therapeutic targets in obesity & diabetes. Mol. Metab. 2019: 19: 86–96. DOI: 10.1016/j.molmet.2018.10.008.

The authors declare that there are no conflicts of interest present.