Open AccessMolecular mechanisms of corticosteroid resistance in patients with chronic obstructive pulmonary disease
Author(s) -
Aliaksei Kadushkin,
А. Д. Таганович
Publication year - 2017
Publication title -
pulʹmonologiâ
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.126
H-Index - 6
eISSN - 2541-9617
pISSN - 0869-0189
DOI - 10.18093/0869-0189-2016-26-6-736-747
Subject(s) - glucocorticoid receptor , protein kinase b , phosphorylation , histone deacetylase 2 , pi3k/akt/mtor pathway , pharmacology , biology , signal transduction , endocrinology , medicine , glucocorticoid , microbiology and biotechnology , histone deacetylase , biochemistry , histone , gene
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.