title: Roflumilast-N-oxide induces surfactant protein expression in human alveolar epithelial cells type II.
abstract: Surfactant proteins (SPs) are important lipoprotein complex components, expressed in alveolar epithelial cells type II (AEC-II), and playing an essential role in maintenance of alveolar integrity and host defence. Because expressions of SPs are regulated by cyclic adenosine monophosphate (cAMP), we hypothesized that phosphodiesterase (PDE) inhibitors, influence SP expression and release. Analysis of PDE activity of our AEC-II preparations revealed that PDE4 is the major cAMP hydrolysing PDE in human adult AEC-II. Thus, freshly isolated human AEC-II were stimulated with two different concentrations of the PDE4 inhibitor roflumilast-N-oxide (3 nM and 1 µM) to investigate the effect on SP expression. SP mRNA levels disclosed a large inter-individual variation. Therefore, the experiments were grouped by the basal SP expression in low and high expressing donors. AEC-II stimulated with Roflumilast-N-oxide showed a minor increase in SP-A1, SP-C and SP-D mRNA mainly in low expressing preparations. To overcome the effects of different basal levels of intracellular cAMP, cyclooxygenase was blocked by indomethacin and cAMP production was reconstituted by prostaglandin E2 (PGE2). Under these conditions SP-A1, SP-A2, SP-B and SP-D are increased by roflumilast-N-oxide in low expressing preparations. Roflumilast-N-oxide fosters the expression of SPs in human AEC-II via increase of intracellular cAMP levels potentially contributing to improved alveolar host defence and enhanced resolution of inflammation.
authors: Division of Internal Medicine, Department of Pneumology, University Medical Centre, Freiburg, Germany.
authors: Kerstin
authors: K
authors: Höhne
authors: Stephan J
authors: SJ
authors: Schliessmann
authors: Andreas
authors: A
authors: Kirschbaum
authors: Till
authors: T
authors: Plönes
authors: Joachim
authors: J
authors: Müller-Quernheim
authors: Hermann
authors: H
authors: Tenor
authors: Gernot
authors: G
authors: Zissel
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology*; D037661:Pulmonary Surfactant-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D037661:Pulmonary Surfactant-Associated Proteins; D012333:RNA, Messenger; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; C517734:roflumilast N-oxide; D015232:Dinoprostone; D007213:Indomethacin