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the underlying basis for the pathology associated with atopic dermatitis (Chan et al.
1993 ). However, soluble PDE4 activity was not increased in a range of peripheral
blood leukocytes from atopic subjects of either mild or severe severity (Gantner
et al. 1997b ). Similarly, while increased total PDE catalytic activity was observed
in peripheral blood monocytes from individuals with mild asthma, this was asso-
ciated, paradoxically, with reduced PDE4 activity (Landells et al. 2001 ), and the
expression of PDE4A, B, and D was not increased in peripheral blood CD4 positive
T-lymphocytes in patients with mild asthma (Jones et al. 2007 ). Together these
studies indicate that the underlying pathogenesis of mild asthma cannot be attrib-
uted to enhanced PDE4 expression or activity. A genome-wide association search
has demonstrated single nucleotide polymorphisms on chromosome 5q12 for PDE4D
(Himes et al. 2009 ).
The significance of these findings remains to be established given that this
isoform is purportedly linked with emesis and targeting of PDE4A and PDE4B is
seen as a rationale approach to develop nonemetic anti-inflammatory PDE4 inhi-
bitors (Manning et al. 1999 ; Kranz et al. 2009 ). If this assertion is correct, then
the challenge remains to develop a PDE4 subtype selective inhibitor that differs by
at least three orders of magnitude, but this has yet to be achieved after more than
a decade of work in this field. However, this hypothesis has been questioned
following the discovery of PDE4D selective allosteric inhibitors, which promote
anti-inflammatory activity and are largely devoid of emesis in animal models (Burgin
et al. 2010 ). The implication of these novel findings is that selectivity for different
PDE4 subtypes is not a critical determinant in avoiding side effects such as nausea,
but whether partial inhibition can be achieved, as in this example using allosteric
inhibitors which interact with upstream conserved regions (UCRs), and the catalytic
domain of PDE4D (Burgin et al. 2010 ).
Numerous preclinical studies in models of allergic pulmonary inflammation
have repeatedly documented the ability of PDE4 inhibitors to inhibit two important
characteristic features of asthma, namely, the recruitment of eosinophils to the
airways and bronchial hyperresponsiveness (Spina 2003 ). One disadvantage of
these studies is the inability to ascertain the role of PDE4 isoforms because of the
nonselective nature of the PDE4 inhibitors currently under development. However,
the use of genetically modified mice has revealed some interesting findings. Airway
inflammation characterized by recruitment of eosinophils to the airways of mice
deficient in PDE4D was not different from that of wild-type controls (Hansen
et al. 2000 ). This indicated that other PDE4 subtypes contribute in the metabolism
of intracellular cAMP since cell recruitment to the airways was inhibited
when animals were treated with nonselective PDE4 inhibitors (Kung et al. 2000 ;
Kanehiro et al. 2001 ). However, airway obstruction caused by methacholine was
enhanced in wild-type allergic mice, but abolished in PDE4D gene-deficient mice.
These mice were hyporesponsive to methacholine, even in the absence of allergic
sensitization, and this feature appeared to be related to an increase in the production
of a dilator prostaglandin in the airways of these PDE4D gene-deficient mice
(Hansen et al. 2000 ; Mehats et al. 2003 ). However, this effect was specific for
methacholine because the enhanced airway obstruction in response to serotonin
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