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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 I\u03baB\u03b1 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-\u03b1-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-\u03b1 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.<\/jats:p>","DOI":"10.1152\/ajplung.00407.2010","type":"journal-article","created":{"date-parts":[[2011,7,23]],"date-time":"2011-07-23T04:56:39Z","timestamp":1311396999000},"page":"L441-L450","source":"Crossref","is-referenced-by-count":25,"title":["NCS 613, a potent and specific PDE4 inhibitor, displays anti-inflammatory effects on human lung tissues"],"prefix":"10.1152","volume":"301","author":[{"given":"Issaka","family":"Yougbare","sequence":"first","affiliation":[{"name":"Le Bilarium, Department of Physiology and Biophysics,"},{"name":"UMR CNRS 7213, Laboratoire de Biophotonique et Pharmacologie, Facult\u00e9 de Pharmacie, Universit\u00e9 de Strasbourg, Illkirch Cedex, 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