Biology Reference
In-Depth Information
Cigarette smoke had been identified to be the relevant inducer of COPD
in industrialised countries and therefore smoke-induced rodent systems were devel-
oped, which are compiled in a recent review (Churg et al.
2008
). Since the rat is the
most sensitive animal species for PDE4 toxicity, it was highly desirable to establish
a smoke-induced rat model, but only a few laboratories succeeded (Lee et al.
2005
).
In cigarette smoke-induced mice or guinea pig models, however, it appeared
that PDE4 inhibitors substantially reduced neutrophil influx into lungs whereas
steroids were without effect (Fitzgerald et al.
2003
, 2006). On the basis of these
experiments, it was demonstrated that 3 days were sufficient to evoke the cell influx
which is typical for COPD and an animal model of smoke-induced pulmonary
inflammation was established (Weidenbach et al.
2008a
), which was resistant to
steroids and served as a routine model for identification of inhibitors of smoke-
induced inflammation.
6.6 COPD Pathomechanisms Overlap with Oral
PDE4 Inhibitor Potential
From the various disease mechanisms discussed for COPD (inflammation, muco-
ciliary malfunction, architectural remodelling and oxidative stress, among others),
COPD-related inflammation is mainly linked with (1) neutrophils, (2) T cells and
(3) macrophages, yet structural cells are another source of inflammatory chemo-
kines, cytokines, arachidonic acid metabolites or ROS. Mucociliary malfunction
may largely be orchestrated by bronchial epithelial cells, yet modulated by numer-
ous inflammatory mediators and tobacco smoke itself. Lung fibroblasts, airway and
pulmonary vascular smooth muscle cells, lung endothelial and bronchial epithelial
cells may account for architectural remodelling (Barnes and Rennard
2008
).
All of these cells express PDE4, and in some cells (such as neutrophils or MCs),
PDE4 is almost exclusively the cAMP-hydrolyzing PDE. As a corollary, PDE4
inhibitors modify a wealth of cellular functions, which may be relevant in COPD
(summarised in Table
8
). For example, in neutrophils PDE4 inhibitors potently
diminish (1) release of superoxide radicals, (2) LTB
4
(Hatzelmann and Schudt
2001
), (3) neutrophil elastase, (4) MMP9 (Jones et al.
2005
), (5) the surface
expression of CD11b (Sanz et al.
2007
) or (6) trans-endothelial migration second-
ary to fMLP. In the same cell, PDE4 inhibitors reduce zymosan-induced (7) release
of IL-8 (Au et al.
1998
) that may act as an autocrine agent to facilitate neutrophil
migration, comparable to LTB
4
. In T cells, inhibitors of PDE4 diminish (1)
proliferation, (2) formation of cytokines such as IFN
g
or IL-2 (Giembycz et al.
1996
; Hatzelmann and Schudt
2001
) or (3) release of granzyme B from CD8+
T cells (Tenor et al.
2005
), among others.
The bronchial epithelial cell is another target of PDE4 inhibitors (Dent et al.
1998
; Fuhrmann et al.
1999
; Mata et al.
2005
). In vitro, exposure to tobacco smoke
extract (1) reduces ciliary beat frequency (CBF) (Cohen et al.
2009
; Simet et al.
2009
),
