Biology Reference
In-Depth Information
vascular injury (Farrow et al.
2008a
,
b
,
2010a
,
b
; Lakshminrusimha et al.
2006
,
2007a
,
b
; Thebaud et al.
2005
; Vento et al.
2001
). As discussed above, PDE5
expression and function may be adversely affected by ROS-mediated events
(Farrow et al.
2008a
,
2010a
,
b
).
Consistent with this hypothesis, three studies address the role of cGMP and
PDE5 in models of preterm lung disease - one study in preterm lambs and two
studies in neonatal rats. In the preterm lamb model of BPD, treatment with a cGMP
analogue that is not hydrolyzable by PDE5 decreased pulmonary vascular resis-
tance, which would indirectly suggest that PDE5 plays a role in the elevated
pulmonary vascular resistance seen with BPD (Bland et al.
2003
). Perhaps more
intriguing are the results seen in the rat model of BPD, induced by hyperoxia. In
that model, treatment of the neonatal rats with sildenafil resulted in decreased
pulmonary vascular resistance, decreased right ventricular hypertrophy (RVH), and
decreased medial wall thickness of pulmonary arteries. This study also showed that
sildenafil improved lung alveolarization, suggesting that PDE5 may play a critical
role in both alveolar and vascular development (Fig.
4
) (Ladha et al.
2005
). A
more recent study in the rat model extends these studies and demonstrated that
treatment with sildenafil prior to hyperoxia exposure increased lung cGMP levels
and improved survival as well as lung alveolarization and angiogenesis. In another
arm of that study, rescue treatment with sildenafil (administration of drug 6 days
after initiation of hyperoxia) significantly decreased pulmonary vessel medial wall
thickness and reduced RVH (de Visser et al.
2009
).
Interesting new data have recently emerged implicating a role for PDE4 in the
pathogenesis of BPD. In one study (de Visser et al.
2008
), preterm rats were
exposed to room air, hyperoxia, or hyperoxia with either of the PDE4 inhibitors,
rolipram or piclamilast (Houslay et al.
2005
). PDE4 inhibition prolonged median
survival and decreased lung inflammation and vascular leakage as well as decreased
markers of inflammation (de Visser et al.
2008
). Another model of BPD, produced
by prolonged exposure of mice to hyperoxia, results in decreased alveolarization
and increased septal wall thickness (Woyda et al.
2009
). Pretreatment with a
PDE4 inhibitor decreased septal wall thickness and increased total airspace area,
suggesting that PDE4 may be of critical importance in neonatal lung development
(Woyda et al.
2009
).
1.3.2 Congenital Heart Disease
Congenital heart disease, particularly that associated with increased pulmonary
arterial blood flow from left-to-right shunts, increased right-sided pressures from
nonrestrictive septal defects and aorto-pulmonary shunts, and increased pulmonary
venous congestion, can lead to remodeling of the pulmonary vascular bed with
associated pulmonary hypertension (Hoffman et al.
1981
). The risk of developing
pulmonary hypertension in these patients is dependent on many factors including
the age of the patient, the type of congenital heart disease, and the degree of
pulmonary overcirculation. Endothelial dysfunction has been hypothesized to
