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 431

Ashwell 2001 ). Furthermore, glucocorticoids are believed to induce the expression
of a number of genes that promote cell cycle arrest and apoptosis in various cell
types (Amsterdam and Sasson 2002 ; Reisman and Thompson 1995 ; Wang et al.
2003 ). Thus, GR-mediated changes in gene expression can produce many of the
wide ranging effects that are normally associated with the anti-inflammatory
actions of glucocorticoids (Clark 2007 ; Newton and Holden 2007 ; Stellato 2004 ).

3.2.3 Enhancement of Glucocorticoid Action by cAMP-Elevating Drugs

Given clinical data showing a clear enhancement of glucocorticoid action by
LABAs, it should be possible to use in vitro models to interrogate forms of
interaction. There are considerable data to suggest that b 2 -adrenoceptor agonists
acting via the cAMP-PKA pathway may repress NF- k B-dependent transcription
and proinflammatory gene expression (Ammit et al. 2002 ; Hallsworth et al. 2001 ;
Kaur et al. 2008b ; Meja et al. 2004 ;Ye 2000 ). While similar repressive effects on
cytokine gene expression are reported with PDE4 inhibitors, such as rolipram
(Seldon et al. 1995 ), these effects vary considerably depending on the cell type,
stimulus, and experimental conditions. Furthermore, it is equally clear that agents
that elevate cAMP can also enhance the expression of certain proinflammatory
genes including granulocyte-colony-stimulating factor, interleukin (IL)-6, and IL-8
(Ammit et al. 2000 , 2002 ; Clarke et al. 2005a, b ; Holden et al. 2010 ). Moreover,
Hertz and colleagues reported in 2009 the results of a microarray study in which
forskolin upregulated 334 genes out of a total 8,530 genes in monocyte-derived
macrophages (Hertz et al. 2009 ). Significantly, CC and CXC chemokines were
strongly induced ( 10-fold) and some, such as CXCL5 ( aka epithelial-derived

neutrophil-activating peptide 78) and CXCL7 ( aka neutrophil-activating peptide 2),
were increased by greater than 50-fold. Similar data were found with rolipram in the
presence of PGE 2 (Hertz et al. 2009 ), indicating that in respiratory diseases, PDE4-
mediated cAMP elevation could, in theory, promote the accumulation of CCR2-
and CXCR2-sensitive cells to the lung and so, paradoxically, enhance pulmonary
inflammation. Thus, an unambiguous argument for anti-inflammatory gain is not
forthcoming and this is consistent with clinical data showing that LABAs, which
also elevate cAMP, are not anti-inflammatory in asthma (Howarth et al. 2000 ;
Roberts et al. 1999 ; Sindi et al. 2009 ). On the basis of these results, it seems likely
that a similar outcome may also apply to the anti-inflammatory potential of other
cAMP-elevating agents such as PDE4 inhibitors when given as a monotherapy .
Indeed, although hints of an anti-inflammatory effect of PDE4 inhibitors have been
reported in patients with COPD (Gamble et al. 2003 ; Grootendorst et al. 2007 ) and
more recently in asthma (Singh et al. 2010 ), the ability of these drugs also to
promote the expression of proinflammatory genes may explain why their predicted
anti-inflammatory potential has not come to fruition.
Despite the lack of demonstrable anti-inflammatory activity of LABAs as
monotherapies (Sindi et al. 2009 ), the superior clinical activity achieved when a
LABA is combined with an ICS is unequivocal when compared to high-dose ICS

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