Harnessing the Clinical Efficacy of Phosphodiesterase 4 Inhibitors in Inflammatory Lung Diseases: Dual-Selective Phosphodiesterase Inhibitors and Novel Combination Therapies - Phosphodiesterases as Drug Targets - page 432

alone (Shrewsbury et al. 2000 ). Thus, the combination therapy provides superior
control of asthma and reduces the frequency of exacerbations, indicating that
the underlying lung inflammation is reduced (Pauwels et al. 1997 ). In an effort to
understand this phenomenon, many investigators have examined the effect of
LABAs and glucocorticoids alone and together on the expression of proinflamma-
tory genes. In almost all cases, the genes selected for study were, typically,
suppressed in an additive manner (reviewed in Newton et al. 2010 , but see Pang
and Knox 2000 ). Consequently, it seems unlikely that the clinical observations
produced by the combination therapy reflect the ability of LABAs (and, by inference,
PDE4 inhibitors) to directly modulate proinflammatory gene expression. Alterna-
tively, it could be argued that the effect of combination therapies on the genes that
would be induced by a LABA or a PDE4 inhibitor may provide some explanation.
Thus, the release of certain cytokines and chemokine from bronchial epithelial cells
and monocyte-derived macrophages is significantly enhanced by LABAs and
PDE4 inhibitors (Hertz et al. 2009 ; Holden et al. 2010 ). However, in the presence
of dexamethasone many of these gene induction events will be abolished or greatly
diminished to the same or a similar extent when the LABA was absent (Holden
et al. 2010 ). If such an effect is seen for the majority of the proinflammatory
genes that are induced by LABAs and PDE4 inhibitors, then these findings could
explain, at least in part, how cAMP-elevating drugs and glucocorticoids repress,
synergistically, proinflammatory gene expression.
While LABAs may promote the recruitment of HDACs to the promoters of
proinflammatory genes (Nie et al. 2005b ), there is little evidence that cAMP
can enhance the ability of glucocorticoids to repress, or trans repress, gene tran-
scription. Consequently, we suggest that such mechanisms may not account for the
superior clinical activity of ICS/LABA combination therapies in asthma and
COPD (Newton et al. 2010 ). Conversely, PKA activation has been shown to
enhance GRE-dependent transcription in a variety of cells types, including proin-
flammatory and immune cells (Rangarajan et al. 1992 ), and this extends to human
bronchial epithelial cells and human airway myocytes with SABAs and LABAs
(Kaur et al. 2008a ). Of prime significance is that “real” glucocorticoid-inducible
genes that have anti-inflammatory potential are also upregulated by LABAs
providing a plausible mechanistic basis for the clinical superiority of LABA/ICS
combination therapies (Giembycz et al. 2008 ). Further support for this concept
is that agonists of the prostacyclin receptor, which typically couples to adenylyl
cyclase, similarly enhance glucocorticoid-dependent transcription of several genes
(e.g., GILZ , MKP-1 , and p57 kip2 ) in bronchial epithelial cells that are predicted to
suppress inflammation (Wilson et al. 2009 ).
In light of the aforementioned discussion, it is possible that a PDE4 inhibitor
could also improve lung function by enhancing the ability of ICSs to induce anti-
inflammatory genes (Giembycz et al. 2008 ). Some evidence for this comes from the
psychiatry and cancer literature. Thus, rolipram has been shown to augment
dexamethasone-induced activation of luciferase reporter genes that were stably
transfected into mouse L929 cells and rat C6 glioma cells (Miller et al. 2002 ).