Phosphodiesterase 6 subunits are expressed and altered in idiopathic pulmonary fibrosis

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)-beta 1 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.