Biology Reference
In-Depth Information
3.3 Role of PDEs in the Inflammation Associated with PAH
Another aspect of PAH that may be targeted by PDE inhibition is the inflammatory
component of the disease. Inflammatory cells such as B- and T cells, dendritic cells
(DCs) and macrophages are all present in the vascular lesions of patients with
IPAH or secondary PAH and in animal models such as the monocrotaline-treated
rat (Hassoun et al.
2009
; Tuder et al.
1994
). PAH is associated with increased
circulating levels of inflammatory mediators such as Il-1
b
and Il-6 and cytokines
and chemokines such as CX3CL1, CCL2, and CCL5 (Balabanian et al.
2002
;
Humbert et al.
1995
; Perros et al.
2007
). Release of these mediators from pulmo-
nary endothelial and PASMC recruit inflammatory cells is hypothesized to initiate
the release of growth factors, increase [Ca
2+
]
i
and transcription and thereby,
to increase remodeling of the PA. Other data have shown that PDE3 and PDE4
regulate cAMP accumulation and proliferation in human CD4+ and CD8+
T-lymphocytes and affect DC function by blocking TNF release, providing evi-
dence that PDE3- and PDE4-inhibitors modulate inflammation [as discussed in
other chapters, (Gantner et al.
1999
; Giembycz et al.
1996
)].
We have shown that the highest expressed PDEs in peripheral blood mononu-
clear cells (PBMCs) are PDE4B, PDE7A, and PDE3B (Zhang et al.
2008
). PDE4,
PDE3, and PDE7 contribute 40, 30, and 15%, respectively, to total-PDE activity in
PASMCs, as determined through a two-step radioassay conducted in the absence or
presence of selective PDE inhibitors. In addition to increasing cAMP in PASMCs
(Millen et al.
2006
; Murray et al.
2007
; Schermuly et al.
2005
), PDE4 inhibitors are
important in modulating the action of immune and inflammatory cells (Souness
et al.
2000
), suggesting that PDE4 inhibitors may help decrease PASMC contrac-
tion and proliferation and also inhibit inflammation that contributes to the develop-
ment of PAH. PDE4A10, PDE4A11, PDE4B2, PDE4C, and PDE4D5 isoforms are
expressed in human PASMCs (Millen et al.
2006
). Of note, the PDE4 inhibitor
piclamilast inhibits proliferation of pulmonary fibroblasts induced by the basic
fibroblast growth factor (bFGF) and low-dose interleukin-1 (IL-1
b
), suggesting
that it may prevent inflammation-induced remodeling of the PA (Selige et al.
2010
). In vivo the PDE4 inhibitor roflumilast decreased mPAP, RV hypertrophy,
and PA muscularization, thereby attenuating the development of monocrotaline-
induced PAH. Roflumilast reduced the increases in IL-6 and monocyte chemotactic
protein-1 (MCP-1) that was observed in lung tissue after 21 days of monocrotaline-
treatment and reversed established monocrotaline-induced PAH, thereby suggest-
ing that blunting of inflammation associated with PAH can help attenuate PA
remodeling (Izikki et al.
2009
).
Since inhibition of PDE4 alone, compared to PDE3 and PDE1, only modestly
decreases PASMC proliferation and increases cAMP accumulation in PAH-
PASMC (Fig.
2a, b
), dual PDE3/PDE4 inhibitors may be a rational therapeutic
