Phosphodiesterase-4 inhibition improves corticosteroid insensitivity in pulmonary endothelial cells under oxidative stress.

6533b7d0fe1ef96bd125ae38

RESEARCH PRODUCT

Phosphodiesterase-4 inhibition improves corticosteroid insensitivity in pulmonary endothelial cells under oxidative stress.

J. L. Ortiz Javier Milara Celia Sanz A. De Diego Julio Cortijo Javier Lluch

subject

medicine.medical_specialty Immunology Apoptosis Dexamethasone Histone Deacetylases Glucocorticoid receptor Receptors Glucocorticoid Adrenal Cortex Hormones Internal medicine medicine Cyclic AMP Immunology and Allergy Humans Receptor Lung Dexamethasone Rolipram Cell Proliferation Histone Acetyltransferases Chemistry Tumor Necrosis Factor-alpha Interleukin-8 Interleukin Phosphodiesterase Endothelial Cells Aparato respiratorio Cyclic Nucleotide Phosphodiesterases Type 4 Enzyme Activation Oxidative Stress Endocrinology Histone deacetylase Phosphodiesterase 4 Inhibitors Pulmones Reactive Oxygen Species Rolipram Glucocorticoid medicine.drug

description

Several clinical studies have shown that smoking in asthmatics and chronic obstructive pulmonary disease patients is closely associated with corticosteroid refractoriness. In this work, we have analyzed glucocorticoid insensitivity in human pulmonary artery endothelial cells (HPAECs) under cigarette smoke extract (CSE) exposure as well as the possible additive effects of the combination therapy with a phosphodiesterase (PDE)-4 inhibitor. Interleukin (IL)-8 was measured in cell supernatants by ELISA. Histone deacetylase (HDAC), histone acetylase (HAT), and intracellular cAMP levels were measured by colorimetric assays and enzyme immunoassay, respectively. PDE4 isotypes and glucocorticoid receptor (GR)-α and β expression were measured by real-time RT-PCR. The PDE4 inhibitor rolipram dose dependently inhibited the IL-8 secretion induced by CSE 5%. In contrast, dexamethasone 1 μM did not show inhibitory effect on IL-8 secretion. Combination of subeffective rolipram concentrations at 10 nM increased the inhibitory effect of dexamethasone to ~45% of inhibition. Cigarette smoke extract 5% inhibited HDAC activity and increased HAT activity generating glucocorticoid insensitivity. Rolipram did not modify the HDAC activity, however partially inhibited the increase in HAT activity at 1 μM. PDE4 isotypes were up-regulated by CSE 5% with the consequent cAMP down-regulation. Dexamethasone reduced all PDE4 isotypes expression and showed additive effects with rolipram enhancing cAMP levels. Furthermore, rolipram enhanced GR-α expression and inhibited the increase in GR-β induced by CSE. Combination of rolipram and dexamethasone shows additive properties in HPAECs under glucocorticoid insensitive conditions. These results may be of potential value in future anti-inflammatory therapies using combination of PDE4 inhibitors and glucocorticoids. SAF2011-26443 FIS CP11/00293 CIBERES (CB06/06/0027) Generalitat Valenciana (Prometeo/2008/45) Generalitat Valenciana (AP-178/11) 5.995 JCR (2013) Q1, 2/21 Allergy, 17/148 Immunology UEV

year	journal	country	edition	language
2012-11-05	Allergy

10.1111/all.12055 https://pubmed.ncbi.nlm.nih.gov/23121078