title: Tiotropium increases PPARγ and decreases CREB in cells isolated from induced sputum of COPD patients.
abstract: 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.
authors: Department of Clinical Pharmacology, Medical University of Bialystok, Bialystok, Poland. holow_sinai@hotmail.com
authors: A
authors: A
authors: Holownia
authors: R M
authors: RM
authors: Mroz
authors: T
authors: T
authors: Skopinski
authors: A
authors: A
authors: Kolodziejczyk
authors: E
authors: E
authors: Chyczewska
authors: J J
authors: JJ
authors: Braszko
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D000068759:Formoterol Fumarate; D006801:Humans; D008176:Lung Volume Measurements; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D047495:PPAR gamma / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012129:Respiratory Function Tests; D012602:Scopolamine Derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D013183:Sputum / Q000737:chemistry / Q000166:cytology; D000069447:Tiotropium Bromide
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001993:Bronchodilator Agents; D017362:Cyclic AMP Response Element-Binding Protein; D004983:Ethanolamines; D018727:Muscarinic Antagonists; D047495:PPAR gamma; D012602:Scopolamine Derivatives; D000068759:Formoterol Fumarate; D000069447:Tiotropium Bromide