Phosphodiesterase 6 subunits are expressed and altered in idiopathic pulmonary fibrosis
Open Access
- 27 October 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Respiratory Research
- Vol. 11 (1), 146
- https://doi.org/10.1186/1465-9921-11-146
Abstract
Background: Idiopathic Pulmonary Fibrosis (IPF) is an unresolved clinical issue. Phosphodiesterases (PDEs) are known therapeutic targets for various proliferative lung diseases. Lung PDE6 expression and function has received little or no attention. The present study aimed to characterize (i) PDE6 subunits expression in human lung, (ii) PDE6 subunits expression and alteration in IPF and (iii) functionality of the specific PDE6D subunit in alveolar epithelial cells (AECs). Methodology/Principal Findings: PDE6 subunits expression in transplant donor (n = 6) and IPF (n = 6) lungs was demonstrated by real-time quantitative (q)RT-PCR and immunoblotting analysis. PDE6D mRNA and protein levels and PDE6G/H protein levels were significantly down-regulated in the IPF lungs. Immunohistochemical analysis showed alveolar epithelial localization of the PDE6 subunits. This was confirmed by qRT-PCR from human primary alveolar type (AT)II cells, demonstrating the down-regulation pattern of PDE6D in IPF-derived ATII cells. In vitro, PDE6D protein depletion was provoked by transforming growth factor (TGF)-β1 in A549 AECs. PDE6D siRNA-mediated knockdown and an ectopic expression of PDE6D modified the proliferation rate of A549 AECs. These effects were mediated by increased intracellular cGMP levels and decreased ERK phosphorylation. Conclusions/Significance: Collectively, we report previously unrecognized PDE6 expression in human lungs, significant alterations of the PDE6D and PDE6G/H subunits in IPF lungs and characterize the functional role of PDE6D in AEC proliferation.This publication has 46 references indexed in Scilit:
- Functional Wnt Signaling Is Increased in Idiopathic Pulmonary FibrosisPLOS ONE, 2008
- Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effectsEye, 2007
- Deletion of PrBP/δ impedes transport of GRK1 and PDE6 catalytic subunits to photoreceptor outer segmentsProceedings of the National Academy of Sciences of the United States of America, 2007
- Emerging drugs for idiopathic pulmonary fibrosisEmerging Drugs, 2005
- Efficacy and Selectivity of Phosphodiesterase-Targeted Drugs in Inhibiting Photoreceptor Phosphodiesterase (PDE6) in Retinal PhotoreceptorsInvestigative Ophthalmology & Visual Science, 2005
- Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertensionThe FASEB Journal, 2005
- RNA interference for HIF-1α inhibits its downstream signalling and affects cellular proliferationBiochemical and Biophysical Research Communications, 2003
- Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF‐β and IL-10European Respiratory Journal, 2003
- The Identification of the Inhibitory γ-Subunits of the Type 6 Retinal Cyclic Guanosine Monophosphate Phosphodiesterase in Non-retinal Tissues: Differential Processing of mRNA TranscriptsGenomics, 2002
- A PDE6A Promoter Fragment Directs Transcription Predominantly in the PhotoreceptorBiochemical and Biophysical Research Communications, 2001