Adenosine-regulated mechanisms in the pathogenesis of ventilation disorders in patients with pulmonary tuberculosis

Cover Page

Cite item


Uncovering involvement of the purinergic system in the pathogenesis of ventilation disorders (VD) may provide additional information about the pathophysiological mechanisms leading to the development of VD in pulmonary tuberculosis (PT). The aim was to identify a relationship between the parameters of adenosine metabolism, inflammatory response and altered ventilation metabolism in PT patients. Materials and methods. Obstructive and mixed PT patients were assigned to subgroups with/without VD for assessing adenosine deaminase activity (ADA-1, 2) in serum, mononuclear cells, neutrophils; ecto-5’-nucleotidase (ecto-5’-NT); CD26 (dipeptidyl peptidase-4, DPP-4), phagocyte oxidative burst measured by NO generation. Results. PT patients showed decreased ADA-1 and CD26 (DPP-4), but increased ADA-2. Elevated intracellular adenosine concentration was found in mononuclear cells in patients lacking VD, whereas patients with mixed and obstructive VD — had it in neutrophils. Mononuclear cells of patients with PT lacking VD as well as with obstructive VD type had decreased NO3– concentration. Neutrophil hyperactivity was recorded in all groups of PT patients. Patients with PT lacking VD as well as with mixed VD type showed that the parameters of external respiration were associated with activity of extra-/intracellular ADA, whereas obstructive VD was caused by excessive formation of serum adenosine. Changes in respiratory function in PT were associated with decreased level of serum NO radicals, impaired nitrogen-dependent bactericidal phagocyte activity, and overproduced neutrophil oxygen radicals. Conclusion. Purinergic regulation is involved in regulating inflammatory and compensatory processes in PT patients as well as impaired ventilation efficiency. The most severe respiratory disorders observed in PT patients with mixed VD type are associated with the most prominent changes in nucleotidase activity, particularly ecto-ADA-2 and DPP-4/CD26.

About the authors

M. E. Dyakova

St. Petersburg Research Institute of Phthisiopulmonology

Author for correspondence.
ORCID iD: 0000-0002-7810-880X

Marina E. Dyakova,  PhD (Biology), Senior Researcher 

194064, St. Petersburg, Ligovskiy pr., 2–4

Phone: +7 921 375-54-32 

Russian Federation

N. B. Serebryanaya

St. Petersburg State University; North-Western State Medical University named after I.I. Mechnikov; Institute of Experimental Medicine

ORCID iD: 0000-0002-2418-9368

PhD, MD (Medicine), Professor of the Department of Cytology and Histology, Faculty of Biology; Professor of the Department of Clinical Mycology, Allergology and Immunology; Leading Researcher, Laboratory of Immunopathophysiology, Department of General Pathology and Pathophysiology

St. Petersburg 

Russian Federation

L. D. Kiryukhina

St. Petersburg Research Institute of Phthisiopulmonology

ORCID iD: 0000-0001-6550-817X

PhD (Medicine), Leading Researcher, Head of the Department of Functional Diagnostics 

Russian Federation

D. S. Esmedlyaeva

St. Petersburg Research Institute of Phthisiopulmonology

ORCID iD: 0000-0002-9841-0061

PhD (Biology), Senior Researcher 

St. Petersburg 

Russian Federation

P. K. Yablonskiy

St. Petersburg Research Institute of Phthisiopulmonology; St. Petersburg State University

ORCID iD: 0000-0003-4385-9643

PhD, MD (Medicine), Professor, Director; Dean of the Medical Faculty 

St. Petersburg 

Russian Federation


  1. Ворончихин Т.А., Аветисян А.О., Васильев И.В., Кудряшов Г.Г., Яблонский П.К. Результаты комплексного лечения ограниченного фиброзно-кавернозного туберкулеза легких // Медицинский Альянс. 2018. № 3. С. 56–64. [Voronchihin T., Avetisyan A., Vasil’ev I., Kudryashov G., Yаblonskiy P. Results of complex treatment of limited fibrous-cavernous pulmonary tuberculosis. Meditsinskiy alyans = Medical Alliance, 2018, no. 3, pp. 56–64. (In Russ.)] doi: 10.36422/23076348-2020-8-1-6-13
  2. Дьякова М.Е. Особенности пуринового метаболизма у больных туберкулезом легких // Патологическая физиология и экспериментальная терапия. 2016. Т. 60, № 3. С.36–42. [Dyakova M.E. Features purine metabolism in patients with pulmonary tuberculosis. Patologicheskaya fiziologiya i eksperimental’naya terapiya = Pathological physiology and experimental therapy, 2016, vol. 60, no. 3, pp. 36–42. (In Russ.)] doi: 10.25557/0031-2991.2016.03.36-41
  3. Дьякова М.Е., Серебряная Н.Б., Кирюхина Л.Д., Эсмедляева Д.С., Яблонский П.К. Аденозин-ассоциированные механизмы в патогенезе хронической обструктивной болезни легких у больных туберкулезом легких // Патогенез. 2019. Т. 17, № 3. С. 47–56. [Dyakova M.E., Serebryanaya N.B., Kiryukhina L.D., Esmedlyaeva D.S., Yablonskiy P.K. Adenosinerelated mechanisms in the pathogenesis of chronic obstructive pulmonary disease in patients with pulmonary tuberculosis. Patogenez = Pathogenesis, 2019, vol.17, no. 3, pp. 47–56. (In Russ.)] doi: 10.25557/2310-0435.2019.03.47-56
  4. Кирюхина Л.Д., Гаврилов П.В., Савин И.Б., Тамм О.А., Володич О.С., Павлова М.В., Арчакова Л.И., Зильбер Э.К., Яблонский П.К. Вентиляционная и газообменная функции легких у больных с локальными формами туберкулеза легких // Пульмонология. 2013. № 6. С. 65–67. [Kiryukhina L.D., Gavrilov P.V., Savin I.B., Tamm O.A., Volodich O.S., Pavlova M.V., Archakova L.I., Zilber E.K., Yablonsky P.K. Ventilation and gas exchange in patients with local forms of pulmonary tuberculosis. Pul’monologiya = Pulmonology, 2013, no. 6, pp. 65–68. (In Russ.)] doi: 10.18093/0869-0189-2013-0-6-807-811
  5. Allen-Gipson D.S., Wong J., Spurzem J.R., Sisson J.H., Wyatt T.A. Adenosine A2A receptors promote adenosine-stimulated wound healing in bronchial epithelial cells. Am. J. Physiol. Lung. Cell Mol. Physiol., 2006, vol. 290, no. 5, pp. L849–L855. doi: 10.1152/ajplung.00373.2005
  6. Antonioli L., Csóka B., Fornai M., Colucci R., Kókai E., Drandizzi C., Haskó G. Adenosine and inflammation: what’s new on the horizon? Drug Discov. Today, 2014, vol. 19, no. 80, pp. 1051–1068. doi: 10.1016/j.drudis.2014.02.010
  7. Antonioli L., Fornai M., Blandizzi C., Pacher P., Haskó G. Adenosine signaling and the immune system: when a lot could be too much. Immunol. Lett., 2019, vol. 205, pp. 9–15. doi: 10.1016/j.imlet.2018.04.006
  8. Cekic C., Linden J. Purinergic regulation of the immune system. Nat. Rev. Immunol., 2016, vol. 16, no. 3, pp. 177–192. doi: 10.1038/nri.2016.4.
  9. Chang X.Y., Yang Y., Jia X.Q., Wang Y., Peng L.N., Ai X.H., Jiang C.Y., Guo J.H., Wu T.T. Expression and clinical significance of serum dipeptidyl peptidase IV chronic obstructive pulmonary disease. Am. J. Med. Sci, 2016, vol. 351, no. 3, pp. 244–252. doi: 10.1016/j.amjms.2015.12.011
  10. Dou L., Chen T.-F., Cowan P.J. Extracellular ATP signaling and clinical relevance. Clin. Immunol., 2018, vol. 188, pp. 67–73. doi: 10.1016/j.clim.2017.12.006.
  11. Eltzschig H.K., Eckle T. Ischemia and reperfusion — from mechanism to translation. Nat. Med., 2011, vol. 17, no.11, pp. 1391–401. doi: 10.1038/nm.250
  12. Faas M.M., Sáez T., de Vos P. Extracellular ATP and adenosine: the Yin and Yang in immune responses? Mol. Aspects Med., 2017, vol. 55, pp. 9–19. doi: 10.1016/j.mam.2017.01.002
  13. Franco R., Pacheco R., Gatell J.M., Gallart T., Lluis C. Enzymatic and extraenzymatic role of adenosine deaminase 1 in T-celldendritic cell contacts and in alterations of the immune function. Crit. Rev. Immunol., 2007, vol. 27, pp. 495–509. doi: 10.1615/critrevimmunol.v27.i6.10
  14. Fredholm B.B. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death and Differ., 2007, vol. 14, pp. 1315–1323. doi: 10.1038/sj.cdd.4402132
  15. Gamble E., Grootendorst D.C., Hattotuwa K., O’Shaughnessy T., Ram F.S., Qiu Y., Zhu J., Vignola A.M., Kroegel C., Morell F., Pavord I.D., Rabe K.F., Jeffery P.K., Barnes N.C. Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis. Eur. Respir. J., 2007, vol. 30, no. 3, pp. 467–471. doi: 10.1183/09031936.00013006
  16. Giusti G. Adenosine deaminase. In: Methods of enzymatic analysis. Volume 2. Ed. by H. Bergmeyer. New York: Academic Press, 1974. pp. 1092–1099.
  17. Jacob F., Novo P., Bachert C., Crombruggen V. Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal., 2013, vol. 9, no. 3, pp. 285–306. doi: 10.1007/s11302-013-9357-4
  18. Karmouty-Quintana H., Xia Y., Blackburn M.R. Adenosine signaling during acute and chronic disease states. J. Mol. Med. (Berl.)., 2013, vol. 91, no. 2, pp. 173–181. doi: 10.1007/s00109-013-0997-1
  19. Kälvegren H., Fridfeldt J., Bengtsson T. The role of plasma adenosine deaminase in chemoattractant-stimulated oxygen radical production in neutrophils. Eur. J. Cell Biol., 2010, vol. 89, no. 6, pp. 462–467. doi: 10.1016/j.ejcb.2009.12.004
  20. Lazarowski E.R. Vesicular and conductive mechanisms of nucleotide release. Purinergic Signal, 2012, vol. 8, no. 3, pp. 359–373. doi: 10.1007/s11302-012-9304-9
  21. Linden J., Cekic C. Regulation of lymphocyte function by adenosine. Arterioscler. Thromb. Vasc. Biol., 2013, vol. 32, no. 9, pp. 2097–2103. doi: 10.1161/ATVBAHA.111.226837
  22. Macintyre N., Crapo R.O., Viegi G., Johnson D.C., van der Grinten C.P., Brusasco V., Burgos F., Casaburi R., Coates A., Enright P., Gustafsson P., Hankinson J., Jensen R., McKay R., Miller M.R., Navajas D., Pedersen O.F., Pellegrino R., Wanger J. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur. Respir. J., 2005, vol. 26, no. 4, pp. 720–735. doi: 10.1183/09031936.05.00034905
  23. Matsuno O., Miyazaki E., Nureki S., Ueno T., Ando M., Kumamoto T. Soluble CD26 is inversely associated with disease severity in patients with chronic eosinophilic pneumonia. Biomark. Insights., 2007, vol. 1, pp. 201–204. doi: 10.1177/117727190600100012
  24. Miller M.R., Hankinson J., Brusasco V., Burgos F., Casaburi R., Coates A., Crapo R., Enright P., van der Grinten C.P., Gustafsson P., Jensen R., Johnson D.C., MacIntyre N., McKay R., Navajas D., Pedersen O.F., Pellegrino R., Viegi G., Wanger J. Standardisation of spirometry. Eur. Respir. J., 2005, vol. 26, no. 2, pp. 319–338. doi: 10.1183/09031936.05.00034805
  25. Pelleg A., Schulman E.S., Barnes P.J. Extracellular adenosine 5’-triphosphate in obstructive airway diseases. Chest, 2016, vol. 150, no. 4, pp. 908–915. doi: 10.1016/j.chest.2016.06.045
  26. Somborac-Bačura A., Buljević S., Rumora L., Čulić O., Detel D., Pancirov D., Popović-Grle S., Varljen J., Čepelak I., Žanić- Grubišić T. Decreased soluble dipeptidyl peptidase IV activity as a potential serum biomarker for COPD. Clin. Biochem., 2012, vol. 45, no. 15, pp. 1245–1250. doi: 10.1016/j.clinbiochem.2012.04.023
  27. Sun C.X., Zhong H., Mohsenin A., Chunn J.L., Molina J.G., Belardinelli L., Zeng D., Blackburn M.R. Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury. J. Clin. Invest., 2006, vol. 116, no. 8, pp. 2173–2182. doi: 10.1172/JCI27303
  28. Tamaki Z., Kubo M., Yazawa N., Mimura Y., Ashida R., Tomita M., Tada Y., Kawashima T., Tamaki K. Serum levels of soluble CD26 in patients with scleroderma. J. Dermatol. Sci., 2008, vol. 52, no. 1, pp. 67–69. doi: 10.1016/j.jdermsci.2008.05.004
  29. Thiel M., Chouker A., Ohta A., Jackson E., Caldwell C., Smith P., Lukashev D., Bittmann I., Sitkovsky M.V. Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLoS Biol., 2005, vol. 3, no. 6, pp. 1088–1100. doi: 10.1371/journal.pbio.0030174
  30. Wanger J., Clausen J.L., Coates A., Pedersen O.F., Brusasco V., Burgos F., Casaburi R., Crapo R., Enright P., van der Grinten C.P., Gustafsson P., Hankinson J., Jensen R., Johnson D., Macintyre N., McKay R., Miller M.R., Navajas D., Pellegrino R., Viegi G. Standardisation of the measurement of lung volumes. Eur. Respir. J., 2005, vol. 26, no. 3, pp. 511–522. doi: 10.1183/09031936.05.00035005
  31. Zavialov A.V., Gracia E., Glaichenhaus N., Franco R., Zavialov A.V., Lauvau G. Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J. Leukoc. Biol., 2010, vol. 88, no. 2, pp. 279–290. doi: 10.1189/jlb.1109764
  32. Zimmermann H., Zebisch M., Strater N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal, 2012, vol. 8, no. 3, pp. 437–502. doi: 10.1007/s11302-012-9309-4

Supplementary files

There are no supplementary files to display.

Copyright (c) 2021 Dyakova M.E., Serebryanaya N.B., Kiryukhina L.D., Esmedlyaeva D.S., Yablonskiy P.K.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies