Tiotropium increases PPARγ and decreases CREB in cells isolated from induced sputum of COPD patients

• Published in: Advances in experimental medicine and biology Vol. 756; p. 9
• Main Authors: Holownia, A, Mroz, R M, Skopinski, T, Kolodziejczyk, A, Chyczewska, E, Braszko, J J
• Format: Journal Article
• Language: English
• Published: United States 01.01.2013
• Subjects: Adrenergic beta-2 Receptor Agonists - pharmacology; Adrenergic beta-2 Receptor Agonists - therapeutic use; Aged; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Bronchodilator Agents - pharmacology; Bronchodilator Agents - therapeutic use; Cell Nucleus - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Cytoplasm - metabolism; Ethanolamines - pharmacology; Ethanolamines - therapeutic use; Female; Forced Expiratory Volume - drug effects; Formoterol Fumarate; Humans; Lung Volume Measurements; Male; Muscarinic Antagonists - pharmacology; Muscarinic Antagonists - therapeutic use; PPAR gamma - metabolism; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Disease, Chronic Obstructive - physiopathology; Respiratory Function Tests; Scopolamine Derivatives - pharmacology; Scopolamine Derivatives - therapeutic use; Signal Transduction; Sputum - chemistry; Sputum - cytology; Tiotropium Bromide
• ISSN: 0065-2598
• DOI: 10.1007/978-94-007-4549-0_2

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and chronic inflammation of airways and lung parenchyma. Our aim was to assess two important elements of intracellular signaling involved in regulation of inflammation in COPD in patients subjected to long-acting beta2-agonist or long-acting beta2-agonist plus long-acting antimuscarinic: peroxisome proliferator-activated receptor gamma (PPARγ) protein, which has antiinflammatory and immunomodulatory properties and cAMP response element binding protein (CREB) and activated (CREB-P) protein which has histone acetyltransferase activity and increases histone acetylation and transcriptional activation of chromatin. Twenty one stable COPD patients (18 males and 3 females, mean age 65 years) receiving 12 μg B.I.D formoterol were assayed before and after 3 month add-on therapy, consisting of 18 μg Q.D. tiotropium. In all patients, sputum induction, spirometry, lung volumes, and DLCO were performed before and after therapy. Sputum cells were isolated and processed to isolate cytosolic and nuclear fractions. PPARγ, CREB, or CREB-P proteins were quantified in subcellular fractions using Western blot. Tiotropium add-on therapy improved respiratory parameters: FEV1 and lung volumes. After therapy mean expression of PPARγ in cell nuclei was significantly increased by about 180%, while CREB and phosphorylated CREB levels in cytosol and nuclei were decreased by about 30%. Our data show that the mechanism whereby tiotropium reduces exacerbations may be associated not only with persistent increase in airway functions and reduced hyperinflation mediated by muscarinic receptors, but also with possible anti-inflammatory effects of the drug, involving increased PPARγ and decreased CREB signaling.