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activity of PDE4A4 was increased and suggested that local events/processes within
the lung of subjects with COPD specifically upregulated this variant (Barber et al.
2004 ). However, the functional consequence of this change remains to be estab-
lished in light of findings showing that PDE4 inhibition has only a modest effect in
suppressing TNF a production from human macrophages derived from cultured
monocytes. Moreover, the contribution of other PDEs (e.g., PDE3, PDE7) and
other PDE4 isoforms in regulating function in this cell type clearly need to be
explored (Gantner et al. 1997a ; Smith et al. 2004 ). Genotyping studies have also
revealed the presence of single nucleotide polymorphisms within the PDE4D gene
in COPD subjects compared with smokers within the Japanese population that was
in linkage disequilibrium with the IL-13 gene. However, the significance of these
findings remains to be established since this relationship was absent in an Egyptian
population (Homma et al. 2006 ).
In vivo models of COPD are very limited. However, the recruitment of
neutrophils to the airways can be readily induced using the bacterial wall
component, endotoxin, although it is widely appreciated that this stimulus can
only model neutrophil recruitment to the airways (Leclerc et al. 2006 ). Neutro-
phil recruitment into the airways of wild-type mice was inhibited by around
50% in PDE4B and PDE4D-deficient mice and a greater degree of inhibition
was observed when wild type mice were treated with rolipram (Ariga et al. 2004 ).
This once again highlights the complementary roles of PDE4 isoforms in reg-
ulating neutrophil recruitment to the airways. Similarly, smoking-induced neu-
trophil recruitment to the airways, release of chemokines, and emphysematous
changes to the lung were attenuated by PDE4 inhibitors (Martorana et al. 2005 ;
Leclerc et al. 2006 ). Together, these studies highlight the utility of inhibiting
PDE4 in cell types implicated in COPD.
A number of phase III clinical trials have assessed the potential utility of PDE4
inhibitors in the treatment of COPD (Rabe et al. 2005 ; Rennard et al. 2006 ;
Calverley et al. 2007 ). All three studies report modest, but nevertheless significant
improvements in spirometry over placebo, quality of life scores, and reduction
in the number of exacerbations in the severest group of COPD subjects. Indeed,
recent phase III clinical trials evaluating the effect of roflumilast in symptomatic
moderate-to-severe asthmatics have reported more promising findings (Fabbri et al.
2009 ; Calverley et al. 2009 ). Roflumilast caused a significant 48-ml improvement
in FEV1 compared with placebo and reduced exacerbation rates of moderate-
to-severe intensity by 17% over a 52-week period (Calverley et al. 2009 ). Similarly,
roflumilast consistently improved baseline FEV1 in moderate-to-severe COPD
patients already taking either a long-acting b 2 -agonist (salmeterol) or a long-acting
muscarinic antagonist (tiotropium bromide) by 49 and 80 ml, respectively, during
24 weeks of treatment (Fabbri et al. 2009 ).
The mechanism of the improvement in spirometry is unlikely to be due to
relaxation of airway smooth muscle because this drug class has weak bronchodila-
tor activity. It is possible that this improvement is due to an anti-inflammatory
action of the drugs (Table 1 ), although no biomarker of inflammation was mea-
sured in these studies. However, separate studies have addressed whether PDE4
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