Biology Reference
In-Depth Information
muscle mass
that is most prevalent in the bronchioles (Aoshiba and Nagai
2004
;
Hogg et al.
2004
; Hossain and Heard
1970
; Jeffery
2001
). This is an important
finding as the major site of obstruction in COPD occurs in the smaller airways
(
2 mm in diameter) (Hogg et al.
2004
).
The possibility that remodeling of the airways may contribute to irreversible
airway obstruction and AHR prompted the pharmaceutical industry to look for
compounds that arrest, or ideally reverse, this process. With respect to the smooth
muscle component, a drug that could prevent mitogenesis could be a therapeutic
advance. In this respect, there is precedent that inhibition of PDE1 could be a viable
target. Evidence for this possibility derives from studies performed using the human
lymphoblastoid RPMI-8392 B-cell line. These cells were established from a patient
with acute lymphocytic leukemia and express two major PDEs: PDE1 (probably
PDE1B) and PDE4 (Epstein et al.
1987
; Jiang et al.
1996
). In contrast, normal
quiescent human B-lymphocytes lack measurable PDE1 (Epstein et al.
1987
;
Gantner et al.
1998
). Following exposure of normal B-lymphocytes to the mitogen,
phytohemagglutinin (PHA), significant PDE1 activity is detected together with
mRNA transcripts for PDE1B (Hurwitz et al.
1990
; Jiang et al.
1996
). The induced
enzyme elutes from anion-exchange columns as a 63-kDa protein that is indistin-
guishable from PDE1B purified from bovine brain (Bentley et al.
1992
; Hurwitz
et al.
1990
). Mitogens are known to promote the transcription of
PDE1B
(Spence
et al.
1995
,
1997
), and it is possible that gene induction occurs when lymphocytes
switch from a quiescent to a proliferative phenotype. As cGMP suppresses lymphocyte
proliferation (Fischer et al.
2001
), the induction of
PDE1B
, which preferentially
hydrolyzes cGMP, by PHA could, by lowering the basal cGMP content, represent a
physiological response to permit B-cell mitogenesis.
Evidence that PDE1 is implicated in human vascular smooth muscle prolifera-
tion is also available (Rybalkin et al.
1997
,
2002
), and it is not unreasonable to
speculate that one or more PDE1 isoenzymes could subserve the same function
in airway myocytes. Rybalkin and colleagues found that of the three genes that
encode PDE1 isoforms (Bender and Beavo
2006
), PDE1C, which hydrolyzes
cAMP and cGMP with similar kinetics, was markedly induced in proliferating
but not quiescent smooth muscle cells derived from human aorta. Like airway
myocytes (Giembycz and Barnes
1991
; Torphy et al.
1991
,
1993
), this enzyme is
the predominant PDE in these cells (Rybalkin et al.
1997
). Subsequently, it was
established that induction of PDE1C correlated with cell cycle progression and
that inhibition of this enzyme with either 8-methoxymethyl-3-isobutyl-1-methyl-
xanthine (a modestly selective PDE1 inhibitor) or antisense oligonucleotides
directed against
PDE1C
significantly reduced mitogenesis (Rybalkin et al.
2002
). As neither zaprinast nor sildenafil (selective PDE5 inhibitors) was anti-
mitogenic in the same system, it was concluded that proliferation, due to PDE1C
induction, involved increased degradation of cAMP rather than cGMP (Rybalkin
et al.
2002
). Collectively, these data indicate that induction of PDE1C lowers
cAMP in vascular myocytes and so relieves an endogenous “brake” allowing
mitogenesis to proceed unhindered. Given that airway remodeling is characteristic
of asthma and COPD (Aoshiba and Nagai
2004
; Jeffery
2001
), dual-selective
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