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.

Roflumilast Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α and Chemokine Production by Human Lung Parenchyma

“…The almost exclusive expression of PDE4 has been described in neutrophils, whereas other PDE isoenzymes (such as PDE3 or PDE1) contribute to the control of intracellular cAMP levels in macrophages, T-cells and structural cells. In line with literature reports [32], our present results indicate that PDE4 accounts for about 38% of the total cAMP hydrolyzing activity in extracts of human lung explants. We found that PDE3 contributed another 27%.…”

Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

“…1 G and H and Fig. S2 A and B) (34,(40)(41)(42). Immunofluorescent staining showed that high intensity of PDE4B immunofluorescence signals was largely detected in bronchial epithelium of mouse lung tissues (Fig.…”

Disease Progression in MRL/lpr Lupus-Prone Mice Is Reduced by NCS 613, a Specific Cyclic Nucleotide Phosphodiesterase Type 4 (PDE4) Inhibitor

“…NCS 613 is a potent and selective inhibitor of PDE4 [11], which induces in vivo and ex vivo anti-inflammatory effects [27], [28]. We recently showed in human lung tissues that NCS 613 significantly decreased PDE4 activity and reduced I-ΚBα degradation with a lower expression level of PDE4B and PDE4C [29]. NCS 613 inhibits LPS-induced TNFα secretion by human PBLs with an IC 50 value of 18 nM [27].…”