Biology Reference
In-Depth Information
Table 8 Isolated cell models for COPD in 2005
Model
Stimulus
Response
PDE
Neutrophils
fMLP
ROS, LTB
4
, HNE, MMP9, CD11b,
chemotaxis, adhesion
4
Zymosan
IL-8
Monocytes
LPS
TNF
a
, LTB
4
4
TNF
a
, ROS, MMPs
Macrophages
LPS
1,3,4
Proliferation, IL2, IFN
g
, Granzyme B
CD8+ T-cells
AntiCD3/
(CD28)
1,3,4
CD4+ T-cells
AntiCD3/
CD28
Proliferation, IL2, IFN
g
1,3,4
Bronchial epithelial cells
TNF
GM-CSF
1,4
None
CFTR
None/TSE
Ciliary beat frequency
TSE/EGF
MUC5AC
Lung fibroblasts
bFGF
Proliferation
1,3,4,5
TGFß1
Myofibroblast transition, CTGF,
fibronectin, collagen I
Fibronectin/
TGFß
Chemotaxis, collagen gel contraction
Airway smooth muscle cells
Serum
Proliferation
1,3,4,5
Pulmonary vascular smooth
muscle cells
Serum
Proliferation, endothelin I
1,3,4,5
Endothelial cells
Thrombin
Hyperpermeability
1,2,3,4
TNF
a
E-selectin
Enriched and purified cell populations have been prepared, which are being used for determination
of PDE inhibitor efficacy in the various facets of COPD pathomechanisms. A multiple array of
read-outs has been established for cells involved in inflammatory, mucociliary, vascular or
proliferative functions. TSE is tobacco smoke extract
(2) impairs CFTR-driven Cl
secretion (Kreindler et al.
2005
; Cantin et al.
2006
;
Cohen et al.
2009
) and (3) augments production of mucus proteins such
as MUC5AC in bronchial epithelial cells altogether accounting for mucociliary
malfunction in COPD (Takeyama et al.
2001
). PDE4 inhibitors in turn (1) increase
CBF and rescue from compromised CBF secondary to tobacco smoke (Cervin
and Lindgren
1998
; Wohlsen et al.
2006
; Milara et al.
2008a
), (2) augment CFTR
activity (Barnes et al.
2005
; Pedemonte and Galietta
2008
) and (3) reduce tobacco
smoke-induced MUC5AC expression (EJ Morcillo, personal communication). As a
corollary from these findings, a PDE4 inhibitor may be expected to mitigate
mucociliary malfunction in COPD.
PDE4 inhibitors further prevent the activation of human lung fibroblasts illu-
strated by a (1) reduction of proliferation, (2) myofibroblast transition, (3) excessive
generation of extracellular matrix (fibronectin, collagen I), (4) chemotaxis, (5)
collagen gel contraction (reflecting scar formation), release of cytokines such as
(6) eotaxin or expression of (7) ICAM-1 cell adhesion molecule (Kohyama et al.
2002
; Boero et al.
2006
; Dunkern et al.
2007
; Klar et al.
2007
; Togo et al.
2009
;
Sabatini et al. 2010). Finally, PDE4 inhibitors attenuate formation of ROS in
structural cells such as human airway epithelial cells, pulmonary vascular smooth
