PHENOTYPIC DIFFERENCES AND PECULIARITIES OF INFLAMMATION IN ASTHMATICS WITH ISOLATED AND COMBINED AIRWAY HYPERRESPONSIVENESS TO COLD AIR AND DISTILLED WATER

A complex examination of 122 patients with bronchial asthma (BA) was done to find out the interrelationship between airway hyperresponsiveness to cold (isocapnic cold air hyperventilation - ICAH) and hyposmolar (ultrasonic nebulized distilled water - UNDW) stimuli, the disturbance of lung function, the character of inflammation in the respiratory tract and immune-metabolic status. All the patients were studied upon the lung function and airway response to cold and osmotic stimuli, the values of oxidative stress, cytokines spectrum (IL-4, IL-5, IL-6, IL-8, IFNγ) in the exhaled breath condensate (EBC) and the blood serum, the level of cortisol and adrenocorticotropic hormone. The functional state of β₂-adrenoreceptive complex of airways was studied by the level of 3ʹ5ʹ-cyclic adenosine monophosphate (cAMP) increase. To find phenotypic differences in the inflammation and immune-metabolic status features, all the patients were divided into 4 groups: the 1^st group (26%) was with airway hyperresponsiveness to both stimuli (cold and osmotic), the 2^nd group (15%) was with airway hyperresponsiveness only to UNDW, the 3^rd group (26%) only to ICAH, the 4^th group (33%) did not have any response to both triggers. Significant differences in the relationship of the respiratory function and main biochemical values were found. In the patients with the response to both stimuli maximal values of the base level of Н₂О₂ and IL-4 in EBC as well as the high level of IL-6 in the blood serum were revealed in comparison with other groups. These patients had a close correlation of TNFα in EBC and the airway response (DFEV₁) to ICAH (r=-0.76; р˂0.05), as well as of bronchi hyperresponsiveness and the contents of cAMP (r=0.70; р˂0.01) in the blood serum, which proved a more severe clinical course of the disease. In the patients of the second group FEV₁ correlated with IL4 contents in EBC (r=-0.48; р˂0.01), and DFEV₁ after UNDW depended on the contents of IL-4 (r=-0.42; р˂0.05) in the blood serum and IL-4/IFNg (r=-0.50; р˂0.05). In the patients of the 3^rd group eosinophilic-neutrophilic type of bronchi inflammation dominated. The initial level of Н₂О₂ production and secondary products oxidation index in EBC was connected with the response of FEV₁ to ICAH (r=-0.49, р˂0.01 and r=0.28, р˂0.05, respectively). The initial FEV₁ correlated with с IL-6 (r=-0.67; р˂0.001) and IL-5 (r=0.84; р˂0.05), and DFEV₁ after ICAH with the level of IFNg (r=-0.65; р˂0.001) in the blood serum. The allergic type of inflammation dominated in the 4^th group, the correlation of FEV₁, secretion of IL-4 in EBC (r=-0.66; р˂0.01) and the quantity of eosinophils in the blood (r=-0.23; р˂0.05) was found. We suggested there are different molecular subtypes of the inflammation reaction in the asthmatics with cold and osmotic airway hyperresponsiveness. They have potential clinical importance and open new possibilities in understanding the mechanisms responsible for the formation of bronchoobstructive syndrome and the prospects of its correction.

бронхиальная астма, гиперреактивность дыхательных путей, холодный воздух, осмотический стимул, воспаление, оксидативный стресс, asthma, airway hyperresponsiveness, cold air, osmotic stimulus, inflammation, oxidative stress

1. Генетический полиморфизм термочувствительных катионных каналов TRPM8 как фактор предрасположенности к холодовой гиперреактивности дыхательных путей у больных хроническими обструктивными заболеваниями легких / Д.Е.Наумов [и др.] // Бюл. физиол. и патол. дыхания. 2012. Вып.45. С.8-14.

2. Покровский В.И., Виноградов Н.А. Оксид азота, его физиологические и патофизиологические свойства // Тер. арх. 2005. №1. С.82-87.

3. Перельман Ю.М., Приходько А.Г. Диагностика холодовой гиперреактивности дыхательных путей: методические рекомендации. Благовещенск, 1998. 8 с.

4. Приходько А.Г., Перельман Ю.М., Колосов В.П. Гиперреактивность дыхательных путей. Владивосток: Дальнаука, 2011. 204 с.

5. Приходько А.Г. Реакция дыхательных путей на гипоосмолярный стимул // Бюл. физиол. и патол. дыхания. 2005. Вып.21. С.47-52.

6. Приходько А.Г., Макарова Г.А. Иммунологические механизмы в инициации и модулировании холодовой реактивности дыхательных путей // Бюл. физиол. и патол. дыхания. 2009. Вып.34. С.13-16.

7. Соодаева С.К. Свободнорадикальные механизмы повреждения при болезнях органов дыхания // Пульмонология. 2012. №1. С.5-10.

8. Ушакова Е.В., Пирогов А.Б., Колосов В.П. Функциональное состояние мембранно-клеточной бета-адренергической рецепции и глюкокортикоидной функции надпочечников у больных бронхиальной астмой // IV Съезд врачей-пульмонологов Сибири и Дальнего Востока: тез. докл. Благовещенск, 2011. С.105-107.

9. Chrousos G.P. The Hypothalamic-Pituitary-Adrenal Axis and Immune-Mediated Inflammation // N. Engl. J. Med. 1995.Vol.332, №20. Р.1351-1363.

10. Dienz O., Rincon M. The effects of IL-6 on CD4 T cell responses // Clin. Immunol. 2009. Vol.130, №1. Р.27-33.

11. Cold temperature induces hypersecretion from normal human bronchial epithelial cells in vitro through a transient receptor potential melastatin 8 (TRPM8)-mediated mechanism / M.C.Li [et al.] // J. Allergy Clin. Immunol. 2011. Vol.128, №3. P.626-634.

12. Lin R.-L., Don Hayes Jr., Lee L.-Y. Bronchoconstriction induced by hyperventilation with humidified hot air: role of TRPV1-expressing airway afferents // J. Appl. Physiol. 2009. Vol.106, №6. Р.1917-1924.

13. General considerations for lung function testing / M.R.Miller [et al.] // Eur. Respir. J. 2005. Vol.26, №1. Р.153-161.

14. Miller G.E., Chen E. Life stress and diminished expression of genes encoding glucocorticoid receptor and beta2-adrenergic receptor in children with asthma // Proc. Natl. Acad. Sci. USA. 2006. Vol.103, №14. P.5496-5501.

15. Interleukin-4 activates large-conductance, calcium-activated potassium (BKCa) channels in human airway smooth muscle cells / G.Martin [et al.] // Exp. Physiol. 2008. Vol.93, №7. Р.908-918.

16. Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function / W.A.Neveu [et al.] // Respir. Res. 2010. Vol.11. Р.28.

17. Inhalation of cold air increases the number of inflammatory cells in the lungs in healthy subjects / K.Larsson [et al.] // Eur. Respir. J. 1998. Vol.12, №4. P.825-830.

18. Endocrine-immune interactions in adrenal function of asthmatic children on inhaled corticosteroids / K.N.Priftis [et al.] // Neuroimmunomodulation. 2009. Vol.16, №5. Р.333-339.

19. Dysregulation of the stress response in asthmatic children / K.N.Priftis [et al.] // Allergy. 2009. Vol.64, №1. P.18-31.

20. Histamine stimulates hydrogen peroxide production by bronchial epithelial cells via histamine H1 receptor and dual oxidase / B.Rada [et al.] // Am. J. Resp. Cell Mol. Biol. 2014. Vol.50, №1. Р.125-134.

21. Rahman I., Adcock I.M. Oxidative stress and redox regulation of lung inflammation in COPD // Eur. Respir. J. 2006. Vol.28, №1. P.219-242.

22. Rubini A. Interleukin-6 and lung inflammation: evidence for a causative role in inducing respiratory system resistance increments // Inflamm. Allergy Drug Targets. 2013. Vol.12, №5. Р.315-321.

23. Human lung epithelial cells express a functional cold-sensing TRPM8 variant / A.S.Sabnis [et al.] // Am. J. Respir. Cell Mol. Biol. 2008. Vol. 39, №4. P. 466-474.

24. Taylor-Clark T.E., Undem B.J. Transduction mechanisms in airway sensory nerves // J. Appl. Physiol. 2006. Vol.101, №3. P.950-959.