title: NCS 613, a potent and specific PDE4 inhibitor, displays anti-inflammatory effects on human lung tissues.
abstract: Chronic inflammation is a hallmark of pulmonary diseases, which leads to lung parenchyma destruction (emphysema) and obstructive bronchiolitis occurring in both chronic obstructive pulmonary disease and asthma. Inflammation is strongly correlated with low intracellular cAMP levels and increase in specific cAMP hydrolyzing activity. The aim of the present study was to investigate the role of the cyclic phosphodiesterase type 4 (PDE4) in human lung and to determine the effects of NCS 613, a new PDE4 inhibitor, on lung inflammation and bronchial hyperresponsiveness. High cAMP-PDE activities were found in the cytosoluble fractions from human lung parenchyma and distal bronchi. PDE4 (rolipram sensitive) represented 40% and 56% of total cAMP-PDE activities in the above-corresponding tissues. Moreover, PDE4A, PDE4B, PDE4C, and PDE4D isoforms were detected in all three subcellular fractions (cytosolic, microsomal, and nuclear) with differential distributions according to specific variants. Pharmacological treatments with NCS 613 significantly decreased PDE4 activity and reduced IκBα degradation in cultured parenchyma, both of which are usually correlated with a lower inflammation status. Moreover, NCS 613 pretreatment potentiated isoproterenol-induced relaxations in human distal bronchi, while reducing TNF-α-induced hyperresponsiveness in cultured bronchi, as assessed in the presence of methacholine, U-46619, or histamine. This reducing effect of NCS 613 on human bronchi hyperresponsiveness triggered by TNF-α was related to a lower expression level of PDE4B and PDE4C, as well as a downregulation of the phosphorylated forms of p38-MAPK, CPI-17, and MYPT-1, which are known to control tone. In conclusion, specific PDE4 inhibitors, such as NCS 613, may represent an alternative and isoform-specific approach toward reducing human lung inflammation and airway overreactivity.
authors.affiliation: Le Bilarium, Department of Physiology and Biophysics, Université de Sherbrooke, QC, Canada.
authors.forename: Issaka
authors.initials: I
authors.lastname: Yougbare
authors.forename: Caroline
authors.initials: C
authors.lastname: Morin
authors.forename: Farid Yannick
authors.initials: FY
authors.lastname: Senouvo
authors.forename: Chantal
authors.initials: C
authors.lastname: Sirois
authors.forename: Roula
authors.initials: R
authors.lastname: Albadine
authors.forename: Claire
authors.initials: C
authors.lastname: Lugnier
authors.forename: Eric
authors.initials: E
authors.lastname: Rousseau
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002458:Cell Fractionation; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism*; D016210:Methacholine Chloride / Q000494:pharmacology; D008875:Middle Aged; D009124:Muscle Proteins; D043263:Myosin-Light-Chain Phosphatase / Q000235:genetics / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020889:Rolipram / Q000494:pharmacology; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016085:Bronchoconstrictor Agents; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D009124:Muscle Proteins; C107507:PPP1R14A protein, human; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D016210:Methacholine Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006632:Histamine; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram