Restoration of Corticosteroid Sensitivity in Chronic Obstructive Pulmonary Disease by Inhibition of Mammalian Target of Rapamycin

Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Several molecular mechanisms have been proposed, such as activations of the phosphoinositide-3-kinase/Akt pathway and p38 mitogen-activated protein kinase. However, the mechanism...

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Vydáno v:	American journal of respiratory and critical care medicine Ročník 193; číslo 2; s. 143 - 153
Hlavní autoři:	Mitani, Akihisa, Ito, Kazuhiro, Vuppusetty, Chaitanya, Barnes, Peter J., Mercado, Nicolas
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Thoracic Society 15.01.2016
Témata:	Adrenal Cortex Hormones - pharmacology Adrenal Cortex Hormones - therapeutic use Aged Drug Resistance - drug effects Drug Resistance - immunology Female Histone Deacetylase 2 - drug effects Histone Deacetylase 2 - physiology Humans Immunosuppressive Agents - immunology Immunosuppressive Agents - pharmacology Immunosuppressive Agents - therapeutic use Male Middle Aged Original Oxidative Stress - drug effects Oxidative Stress - physiology p38 Mitogen-Activated Protein Kinases - drug effects p38 Mitogen-Activated Protein Kinases - physiology Phosphatidylinositol 3-Kinases - drug effects Phosphatidylinositol 3-Kinases - physiology Proto-Oncogene Proteins c-akt - drug effects Proto-Oncogene Proteins c-akt - physiology Proto-Oncogene Proteins c-jun - drug effects Proto-Oncogene Proteins c-jun - physiology Pulmonary Disease, Chronic Obstructive - drug therapy Pulmonary Disease, Chronic Obstructive - immunology Pulmonary Disease, Chronic Obstructive - physiopathology Sirolimus - immunology Sirolimus - pharmacology Sirolimus - therapeutic use Smoking - adverse effects Smoking - physiopathology TOR Serine-Threonine Kinases - drug effects TOR Serine-Threonine Kinases - physiology U937 Cells - drug effects c-Jun mammalian target of rapamycin corticosteroid resistance chronic obstructive pulmonary disease rapamycin
ISSN:	1073-449X, 1535-4970, 1535-4970
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Popis
Shrnutí:	Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Several molecular mechanisms have been proposed, such as activations of the phosphoinositide-3-kinase/Akt pathway and p38 mitogen-activated protein kinase. However, the mechanism for corticosteroid resistance is still not fully elucidated. To investigate the role of mammalian target of rapamycin (mTOR) in corticosteroid sensitivity in COPD. The corticosteroid sensitivity of peripheral blood mononuclear cells collected from patients with COPD, smokers, and nonsmoking control subjects, or of human monocytic U937 cells exposed to cigarette smoke extract (CSE), was quantified as the dexamethasone concentration required to achieve 30% inhibition of tumor necrosis factor-α-induced CXCL8 production in the presence or absence of the mTOR inhibitor rapamycin. mTOR activity was determined as the phosphorylation of p70 S6 kinase, using Western blotting. mTOR activity was increased in peripheral blood mononuclear cells from patients with COPD, and treatment with rapamycin inhibited this as well as restoring corticosteroid sensitivity. In U937 cells, CSE stimulated mTOR activity and c-Jun expression, but pretreatment with rapamycin inhibited both and also reversed CSE-induced corticosteroid insensitivity. mTOR inhibition by rapamycin restores corticosteroid sensitivity via inhibition of c-Jun expression, and thus mTOR is a potential novel therapeutic target for COPD.
Bibliografie:	SourceType-Scholarly Journals-1 ObjectType-General Information-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	1073-449X 1535-4970 1535-4970
DOI:	10.1164/rccm.201503-0593OC