pulmoПульмонологияPULMONOLOGIYA0869-01892541-9617Scientific and Practical Journal “PULMONOLOGIYA” LLCpulmo-2703Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL STUDIESКлеточные механизмы взаимодействия лекарственных препаратов при лечении бронхиальной астмы: роль геномных и внегеномных сигнальных системCellular mechanisms of drug interaction in bronchial asthma therapy: a role of genomic and extragenomic signaling systemsОрловС. Н.OrlovS. N.РяжскийГ. Г.RyazhskyG. G.

Москва

СоколовА. С.SokolovA. S.

Москва

ЧучалинА. Г.ChuchalinA. G.

Москва

Научно-исследовательский центр университета г. Монреаль; Лаборатория физико-химии биомембран биологического факультета МГУ им. М.В.ЛомоносоваCanadaИнститут пульмонологии Минздрава РФRussian Federation200308092021015662Copyright © Орлов С.Н., Ряжский Г.Г., Соколов А.С., Чучалин А.Г., 20212021Орлов С.Н., Ряжский Г.Г., Соколов А.С., Чучалин А.Г.Orlov S.N., Ryazhsky G.G., Sokolov A.S., Chuchalin A.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.pulmonology.ru/pulm/article/view/2703

В настоящей работе рассмотрены данные о клеточных механизмах взаимодействия агонистов β-адренергических рецепторов и глюкокортикоидов, которые составляют основу успешной терапии бронхиальной астмы, отмеченной при совместной ингаляции этих соединений. Мы приводим данные о том, что помимо ингибирования киназы легких цепей миозина β-агонисты могут влиять на гладкомышечные клетки (ГМК) через модуляцию активности Са2+-каналов, опосредованную белками цитоскелета, и регулировать контрактуру ГМК вне зависимости от протеинкиназы А. Более того, подобно стероидным гормонам β-агонисты способны вызывать экспрессию генов и контролировать развитие программируемой смерти клеток (апоптоза). В свою очередь стероидные гормоны могут быть вовлечены в патогенез бронхиальной астмы, минуя экспрессию генов, контролирующих протекание воспалительной реакции, в то время как β-агонисты оказывают влияние на формирование воспалительного процесса через генерацию внеклеточного цАМФ и аденозина.

The present review discusses data on cellular mechanisms of interaction of beta-adrenergic agonists and glucocorticoids which are a basis of beneficial asthma therapy being inhaled in common. We show that besides inhibition of myosin light chains beta-agonists can influence the smooth muscle cells modulating the Ca2+-channels’ activity due to cytoskeleton's proteins, and regulate the smooth muscle cell contraction independently on proteinkinase A. Moreover, the beta-agonists are able to stimulate gene expression and to control the initiation of programme cell death (apoptosis) like steroid hormones do. In turn the steroids can beinvolved to the pathogenesis of bronchial asthma without the expression of genes controlling inflammatory reactions, while the beta-agonists effect the inflammation via production of extracellular cyclic AMP and adenosine.

ReferencesОрлов С.Н., Баранова И.А., Покудин Н.И. Гладкомышечные клетки: внутриклеточные системы сигнализации и патология легких. В кн.: Чучалин А.Г. (ред.) Бронхиальная астма. М.: Агар; 1997; т.1: 52-67.Орлов С.Н., Баранова И.А., Покудин Н.И. Гладкомышечные клетки: внутриклеточные системы сигнализации и патология легких. В кн.: Чучалин А.Г. (ред.) Бронхиальная астма. М.: Агар; 1997; т.1: 52-67.Орлов С.Н., Баранова И.А., Чучалин А.Г. Внутриклеточные системы сигнализации и патология легких. I. Гладкомышечные клетки. Пульмонология 1995; 2: 73-77.Орлов С.Н., Баранова И.А., Чучалин А.Г. Внутриклеточные системы сигнализации и патология легких. I. Гладкомышечные клетки. Пульмонология 1995; 2: 73-77.Anderson G.P. Interactions between corticosteroids and P-adrenergic agonists in asthma disease induction, progression, and exacerbation. Am. J. Respir. Crit. Care Med. 2000; 161: S 188—S 196.Anderson G.P. Interactions between corticosteroids and P-adrenergic agonists in asthma disease induction, progression, and exacerbation. Am. J. Respir. Crit. Care Med. 2000; 161: S 188—S 196.Aranda A., Pascual A. Nuclear hormone receptors and gene expression. Physiol. Rev. 2001; 81: 1269-1304.Aranda A., Pascual A. Nuclear hormone receptors and gene expression. Physiol. Rev. 2001; 81: 1269-1304.Barnes P.J. Scientific rationale for inhaled combination therapy with long-lasting p2-agonists and corticosteroids. Eur. Respir. J. 2002; 19: 182-191.Barnes P.J. Scientific rationale for inhaled combination therapy with long-lasting p2-agonists and corticosteroids. Eur. Respir. J. 2002; 19: 182-191.Barnes P.J. The role of inflamation and anti-inflammatory medication in asthma. Respir. Med. 2002; 96 (suppl. A): S9-S15.Barnes P.J. The role of inflamation and anti-inflammatory medication in asthma. Respir. Med. 2002; 96 (suppl. A): S9-S15.Brutsche M.H., Brutsche I.C., Wood P. et al. Apoptosis signals in atopy and asthma measured with cDNA arrays. Clin. Exp. Immunol. 2001; 123: 181-187.Brutsche M.H., Brutsche I.C., Wood P. et al. Apoptosis signals in atopy and asthma measured with cDNA arrays. Clin. Exp. Immunol. 2001; 123: 181-187.Chang H.S., Jeon K.W., Kim Y.H. et al. Role of cAMP-dependent pathway in eosinophil apoptosis and survival. Cell Immunol. 2000; 203: 29-38.Chang H.S., Jeon K.W., Kim Y.H. et al. Role of cAMP-dependent pathway in eosinophil apoptosis and survival. Cell Immunol. 2000; 203: 29-38.Chen Y.Z., Qiu J. Possible genomic consequence of nongenomic action of glucocorticoids in neural cells. News Physiol. Sci. 2002; 16: 292-296.Chen Y.Z., Qiu J. Possible genomic consequence of nongenomic action of glucocorticoids in neural cells. News Physiol. Sci. 2002; 16: 292-296.Chen Y.Z., Qiu J. Pleiotropic signaling pathways in rapid, nongenomic action of glucocorticoids in mammalian neurons. Mol. Cell. Biol. Res. Commun. 1999; 2: 145-149.Chen Y.Z., Qiu J. Pleiotropic signaling pathways in rapid, nongenomic action of glucocorticoids in mammalian neurons. Mol. Cell. Biol. Res. Commun. 1999; 2: 145-149.Coulon V., Blanchard J.-M. Flux calciques et expression genigue. Med. Sei. 2001; 17: 969-978.Coulon V., Blanchard J.-M. Flux calciques et expression genigue. Med. Sei. 2001; 17: 969-978.Cushley M.J., Tallant N.. Holgate S.T. The effect of dipyridamole on histamine- and adenosine-induced bronchoconstriction in normal and asthmatic subjects. Eur. J. Respir. Dis. 1985; 67: 185-192.Cushley M.J., Tallant N.. Holgate S.T. The effect of dipyridamole on histamine- and adenosine-induced bronchoconstriction in normal and asthmatic subjects. Eur. J. Respir. Dis. 1985; 67: 185-192.Dorscheid R.R., Wojcik K.R., Sun S., Marroquin B. et al. Apoptosis of airway epithelial cells induced by corticosteroids. Am. J. Respir. Crit. Care Med. 2001; 164: 1939-1947.Dorscheid R.R., Wojcik K.R., Sun S., Marroquin B. et al. Apoptosis of airway epithelial cells induced by corticosteroids. Am. J. Respir. Crit. Care Med. 2001; 164: 1939-1947.Feoktistov I., Biaggioni I. Role of adenosine in asthma. Drug Dev. Res. 1996; 39: 333-336.Feoktistov I., Biaggioni I. Role of adenosine in asthma. Drug Dev. Res. 1996; 39: 333-336.Fredholm B.B., Abbracchio M .P., Burnstock G. et al. Nomenclature and classification of purinoceptors. Pharmacol. Rev. 1994; 46: 143-156.Fredholm B.B., Abbracchio M .P., Burnstock G. et al. Nomenclature and classification of purinoceptors. Pharmacol. Rev. 1994; 46: 143-156.Gordon J.L. Extracellular ATP: effects, sources and fate. Biochem. J. 1986; 233: 309-319.Gordon J.L. Extracellular ATP: effects, sources and fate. Biochem. J. 1986; 233: 309-319.Holgate S.T. Adenosine: a key molecule of asthma or just another mediator? Am. J. Physiol. Lung Cell. Mol. Physiol. 2002; 282: L167-L168.Holgate S.T. Adenosine: a key molecule of asthma or just another mediator? Am. J. Physiol. Lung Cell. Mol. Physiol. 2002; 282: L167-L168.Holtzm an M.J., Green J.M ., Jayaram an S., Arch R.H. Regulation of T cell apoptosis. Apoptosis 2000; 5: 459-471.Holtzm an M.J., Green J.M ., Jayaram an S., Arch R.H. Regulation of T cell apoptosis. Apoptosis 2000; 5: 459-471.Holtzman M.J., Morton i.D., Shornick L.P. et al. Immunity, inflammation, and remodeling in the airway epithelial barrier: epithelial-viral-allergic paradigm. Physiol. Rev. 2002; 82: 19-46.Holtzman M.J., Morton i.D., Shornick L.P. et al. Immunity, inflammation, and remodeling in the airway epithelial barrier: epithelial-viral-allergic paradigm. Physiol. Rev. 2002; 82: 19-46.Jun C.D., Pae H.O., Yoo J.C. et al. Cyclic adenosine monophosphate inhibits nitric oxide-induced apoptosis in human leukemic HL-60 cells. Cell. Immunol. 1998; 183: 13-21.Jun C.D., Pae H.O., Yoo J.C. et al. Cyclic adenosine monophosphate inhibits nitric oxide-induced apoptosis in human leukemic HL-60 cells. Cell. Immunol. 1998; 183: 13-21.Kankaanranta H., Lindsay M .A., Giembycz M .A. et al. Delayed eosinophil apoptosis in asthma. J. Allergy Clin. Immunol. 2000; 106: 77-83.Kankaanranta H., Lindsay M .A., Giembycz M .A. et al. Delayed eosinophil apoptosis in asthma. J. Allergy Clin. Immunol. 2000; 106: 77-83.Lee M.-R., Liou M.-L., Yang Y.-F., Lai M .-Z. cAMP analogue prevent activation-induced apoptosis of T cell hybridomas. J. Immunol. 1993; 151: 5208-5217.Lee M.-R., Liou M.-L., Yang Y.-F., Lai M .-Z. cAMP analogue prevent activation-induced apoptosis of T cell hybridomas. J. Immunol. 1993; 151: 5208-5217.Luo Y., Lai W., Xu J. Pole of salbutamol in inducing apoptosis of cultured human airway smooth muscle cells. Zhonghua Jie He He Hu Xi Za Zhi 2001; 24: 219-224.Luo Y., Lai W., Xu J. Pole of salbutamol in inducing apoptosis of cultured human airway smooth muscle cells. Zhonghua Jie He He Hu Xi Za Zhi 2001; 24: 219-224.McDonald T.F., Pelzer S., Trautwein W., Pelzer D.J. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol. Rev. 1994; 74: 365-412.McDonald T.F., Pelzer S., Trautwein W., Pelzer D.J. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol. Rev. 1994; 74: 365-412.Nakamura M., Sunagawa M., Kosugi T., Sperelakis N. Actin filament disruption inhibits L-type Ca2+ channel current in cultured vascular smooth muscle cells. Am. J. Physiol. Cell Physiol. 2000; 279: C480-C487.Nakamura M., Sunagawa M., Kosugi T., Sperelakis N. Actin filament disruption inhibits L-type Ca2+ channel current in cultured vascular smooth muscle cells. Am. J. Physiol. Cell Physiol. 2000; 279: C480-C487.Nelson H.S. Advair: combination treatment with fluticasone propionate/salmeterol in the treatment of asthma. J. Allergy Clin. Immunol. 2001; 107: 398-416.Nelson H.S. Advair: combination treatment with fluticasone propionate/salmeterol in the treatment of asthma. J. Allergy Clin. Immunol. 2001; 107: 398-416.Nyce J.W., Metzger W.J. DNA antisense therapy for asthma in an animal model. Nature 1997; 385: 721-725.Nyce J.W., Metzger W.J. DNA antisense therapy for asthma in an animal model. Nature 1997; 385: 721-725.Ohta A., Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 2001; 414: 916-920.Ohta A., Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 2001; 414: 916-920.Orlov S.N ., Maximova N. V. Efflux of cyclic adenosine monophosphate from cells: mechanisms and physiological implications. Biochemistry (Moscow) 1999; 64: 127-135.Orlov S.N ., Maximova N. V. Efflux of cyclic adenosine monophosphate from cells: mechanisms and physiological implications. Biochemistry (Moscow) 1999; 64: 127-135.Orlov S.N., Thorin-Trescases N., Dulin N.O. et al. Activation of cAMP signaling transiently inhibits apoptosis in vascular smooth muscle cells in a site upstream of caspase 3. Cell Death Different. 1999; 6: 691-672.Orlov S.N., Thorin-Trescases N., Dulin N.O. et al. Activation of cAMP signaling transiently inhibits apoptosis in vascular smooth muscle cells in a site upstream of caspase 3. Cell Death Different. 1999; 6: 691-672.Orlov S.N., Tremblay J., Hamet P. cAMP signaling inhibits dihydropyridine-sensitive Ca2+ influx in vascular smooth muscle cells. Hypertension 1996; 27: 774-780.Orlov S.N., Tremblay J., Hamet P. cAMP signaling inhibits dihydropyridine-sensitive Ca2+ influx in vascular smooth muscle cells. Hypertension 1996; 27: 774-780.Orlov S.N., Tremblay J., Hamet P. Cell volume in vascular smooth muscle is regulated by bumetanide-sensitive ion transport. Am. J. Physiol. 1996; 270: C1388-C1397.Orlov S.N., Tremblay J., Hamet P. Cell volume in vascular smooth muscle is regulated by bumetanide-sensitive ion transport. Am. J. Physiol. 1996; 270: C1388-C1397.Orlov S.N., Tremblay J., Hamet P. Altered (3-adrenergic regulation of Na-K-Cl cotransport in cultured smooth muscle cells from the aorta of spontaneously hypertensive rats. Am. J. Hypertens. 1995; 8: 739-747.Orlov S.N., Tremblay J., Hamet P. Altered (3-adrenergic regulation of Na-K-Cl cotransport in cultured smooth muscle cells from the aorta of spontaneously hypertensive rats. Am. J. Hypertens. 1995; 8: 739-747.Palmqvist М., Arvidsson P., Beckman O. et al. Onset of bronchodilation of budesonide/formoterol vs salmeterol/fluticasone in single inhalers. Pulm. Pharmacol. 2001; 14: 29-34.Palmqvist М., Arvidsson P., Beckman O. et al. Onset of bronchodilation of budesonide/formoterol vs salmeterol/fluticasone in single inhalers. Pulm. Pharmacol. 2001; 14: 29-34.Parvathenani L.K., Buescher E.S., Chacon-Cruz E., Beebe S.J. Type I cAMP-dependent protein kinase delays apoptosis in human neutrophils at a site upstream of caspase-3. J. Biol. Chem. 1998; 273: 6736-6743.Parvathenani L.K., Buescher E.S., Chacon-Cruz E., Beebe S.J. Type I cAMP-dependent protein kinase delays apoptosis in human neutrophils at a site upstream of caspase-3. J. Biol. Chem. 1998; 273: 6736-6743.Piliponsky A.M ., Levi-Schaffer F. Regulation of apoptosis in mast cells. Apoptosis 2000; 5: 435-441.Piliponsky A.M ., Levi-Schaffer F. Regulation of apoptosis in mast cells. Apoptosis 2000; 5: 435-441.Sandrasagra A., Tang L., Leonard S.A. et al. RASONs: a novel antisense oligonucleotide therapeutic approach for asthma. Expert Opin. Biol. Ther. 2001; 1: 979-983.Sandrasagra A., Tang L., Leonard S.A. et al. RASONs: a novel antisense oligonucleotide therapeutic approach for asthma. Expert Opin. Biol. Ther. 2001; 1: 979-983.Sciorati C., Rovere P., Ferrarini M. et al. Autocrine nitric oxide modulates CD95-induced apoptotsis in gamma-delta T lymphocytes. J. Biol. Chem. 1997; 272: 23211-23215.Sciorati C., Rovere P., Ferrarini M. et al. Autocrine nitric oxide modulates CD95-induced apoptotsis in gamma-delta T lymphocytes. J. Biol. Chem. 1997; 272: 23211-23215.Skriabin G., Orlov S.N., Masse C., Berthiaume Y. Phloretin inhibits Na+ and K+ uptake in cultured alveolar type II cells by reduction of cellular ATP content. Exp. Lung Res. 2000; 26: 319-333.Skriabin G., Orlov S.N., Masse C., Berthiaume Y. Phloretin inhibits Na+ and K+ uptake in cultured alveolar type II cells by reduction of cellular ATP content. Exp. Lung Res. 2000; 26: 319-333.Spicuzza L., Belvisi М., Birell M.A. et al. Evidence that the anti-spasmogenic effect effect of the P-adrenoceptor agonist, isoprenaline, onguinea-pig trachealis is not mediated by cyclic AMP-dependent protein kinase. Br. J. Pharmacol. 2001; 133: 1201- 1212.Spicuzza L., Belvisi М., Birell M.A. et al. Evidence that the anti-spasmogenic effect effect of the P-adrenoceptor agonist, isoprenaline, onguinea-pig trachealis is not mediated by cyclic AMP-dependent protein kinase. Br. J. Pharmacol. 2001; 133: 1201- 1212.Taurin S., Ryazhski G.G., Maximova N.V. et al. Suppression of programmed cell death by intracellular cAMP is not mediated by expression of genes encoding an inhibitor of apoptosis. Biochemistry (Moscow) 2002; 67: 303-310.Taurin S., Ryazhski G.G., Maximova N.V. et al. Suppression of programmed cell death by intracellular cAMP is not mediated by expression of genes encoding an inhibitor of apoptosis. Biochemistry (Moscow) 2002; 67: 303-310.Thorin-Trescases N., Orlov S.N ., Taurin S. et al. Antiproliferative effect of brief exporsure to cholera toxin in vascular smooth muscle cells: role of cAMP and protein kinase A. Can. J. Physiol. Pharamacol. 2001; 79: 471-480.Thorin-Trescases N., Orlov S.N ., Taurin S. et al. Antiproliferative effect of brief exporsure to cholera toxin in vascular smooth muscle cells: role of cAMP and protein kinase A. Can. J. Physiol. Pharamacol. 2001; 79: 471-480.Vignola A.M ., Chiappara G., Gagliardo R. et al. Apoptosis and airway inflammation in asthma. Apoptosis 2000; 5: 473-485.Vignola A.M ., Chiappara G., Gagliardo R. et al. Apoptosis and airway inflammation in asthma. Apoptosis 2000; 5: 473-485.Walsh G.M. Eosinophil apoptosis: mechanisms and clinical relevance in asthmatic and allergic inflammation. Br. J. Haematol. 2000; 111: 61-67.Walsh G.M. Eosinophil apoptosis: mechanisms and clinical relevance in asthmatic and allergic inflammation. Br. J. Haematol. 2000; 111: 61-67.

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