pulmoПульмонологияPULMONOLOGIYA0869-01892541-9617Scientific and Practical Journal “PULMONOLOGIYA” LLC10.18093/0869-0189-2016-26-6-736-747pulmo-798Research ArticleОБЗОРЫREVIEWМолекулярные механизмы формирования стероидорезистентности у пациентов с хронической обструктивной болезнью легкихMolecular mechanisms of corticosteroid resistance in patients with chronic obstructive pulmonary diseaseКадушкинА. Г.KadushkinA. G.

220116, Республика Беларусь, Минск, пр. Дзержинского, 83

к. м. н., ассистент кафедры биологической химии Учреждения образования «Белорусский государственный медицинский университет»; тел.: (8017) 2726788

pr. Dzerzhinskogo 83, Minsk, 220116, Belarus

Candidate of Medicine, Assistant Lecturer at Department of Biological Chemistry, Belarusian State Medical University, tel.: (8017) 2726788

kadushkyn@gmail.comТагановичА. Д.TaganovichA. D.

220116, Республика Беларусь, Минск, пр. Дзержинского, 83

д. м. н., профессор, заведующий кафедрой биологической химии Учреждения образования «Белорусский государственный медицинский университет»; тел.: (8017) 2726764

pr. Dzerzhinskogo 83, Minsk, 220116, Belarus

Doctor of Medicine, Professor, Head of Department of Biological Chemistry, Belarusian State Medical University, tel.: (8017) 2726764

taganovich@bsmu.byУчреждение образования «Белорусский государственный медицинский университет»РоссияBelarus State Medical UniversityRussian Federation201628022017266736747Copyright © Кадушкин А.Г., Таганович А.Д., 20172017Кадушкин А.Г., Таганович А.Д.Kadushkin A.G., Taganovich A.D.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/798

В настоящее время для терапии хронической обструктивной болезни легких (ХОБЛ) широко применяются ингаляционные глюкокортикостероиды (иГКС), поскольку они способны оказывать противовоспалительное действие. Однако их эффективность при ХОБЛ значительно ограничена. К молекулярным механизмам развития стероидорезистентности (СР) относятся нарушение связывания и транслокации ГКСрецептора (ГР) в ядро, повышенная экспрессия изоформы ГРβ, увеличение экспрессии фактора, ингибирующего миграцию макрофагов (macrophage migration inhibitory factor (MIF)), снижение экспрессии фосфатазы1 митогенактивируемой протеинкиназы (MKP1) и гистондеацетилазы2 (ГДА2). Снижение экспрессии и активности ГДА2, которая вовлечена в ингибирование ГКС генов провоспалительных цитокинов, является результатом окислительного и нитрозативного стресса, развивающихся в ответ на вдыхание сигаретного дыма. При этом окислительный стресс приводит к активации фосфатидилинозитол3киназыδ (ФИ3Кδ). Дальнейший путь передачи сигнала от ФИ3Кδ включает фосфорилирование (активацию) киназы Akt, фосфорилирование (ингибирование) киназы гликогенсинтазы3β и фосфорилирование (инактивацию) ГДА2. Сведения о механизмах формирования СР позволили выявить лекарственные препараты, оказывающие влияние на патогенетические звенья этого состояния. Так, антидепрессант нортриптилин и макролид солитромицин преодолевают СР, ингибируя фосфорилирование Akt. Комбинация ГКС и длительно действующего β2аго ниста увеличивает транслокацию ГР в ядро клетки и ингибирует фосфорилирование Akt. Ингибитор фосфодиэстеразы4 рофлумиласт в сочетании с дексаметазоном восстанавливает чувствительность клеток к ГКС за счет изменения экспрессии ФИ3Kδ, ГДА2, MKP1, MIF и ГРβ. Раскрытие молекулярных механизмов СР позволяет усилить противовоспалительные свойства ГКС и улучшить эффективность лечения ХОБЛ.

Glucocorticoids are widely used for the treatment of chronic obstructive pulmonary disease (COPD) because of their antiinflammatory properties. However, their therapeutic effectiveness is significantly limited in COPD. Molecular mechanisms of steroid resistance include defective glucocorticoid receptor (GR) binding and translocation into the nucleus, increased expression of GRβ isoform, elevated expression of macrophage migration inhibitory factor (MIF), decreased expression of mitogenactivated protein kinase phosphatase 1 (MKP1) and histone deacetylase 2 (HDAC2). HDAC2 is involved in suppression of inflammatory genes by glucocorticoids, and its reduced activity and expression are the result of oxidative and nitrative stress induced by cigarette smoke. Oxidative stress causes activation of phosphoinositide3kinase δ (PI3Kδ) which leads to phosphorylation (activation) of Akt kinase, phosphorylation (inhibition) of glycogen synthase kinase 3β and phosphorylation (inactivation) of HDAC2. Understanding of the mechanisms leading to steroid resistance allowed identification drugs targeting this condition. Antidepressant nortriptyline and macrolide solithromycin reverse corticosteroid resistance through inhibition of Akt phosphorylation. Combination of glucocorticoid and longacting β2agonist increases GR nuclear translocation and inhibits Akt phosphorylation. The phosphodiesterase 4 inhibitor roflumilast in combination with dexamethasone improves steroid responsiveness through modulation of PI3Kδ, HDAC2, MKP1, MIF and GRβ expression. Investigation of the molecular mechanisms of steroid resistance can increase antiinflammatory properties of steroids and lead to more effective COPD treatment.

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