Biology Reference
In-Depth Information
specifically dysregulated in MAS. Interestingly, a recent study demonstrated that
sildenafil is a potent pulmonary vasodilator in a neonatal piglet model of MAS
(Shekerdemian et al.
2002
,
2004
).
1.2.2
Idiopathic PPHN
Idiopathic PPHN is the second most common etiology of PPHN and is classically
described in near-term (
34 weeks gestation) and term newborns (Konduri
2004
;
Walsh-Sukys et al.
2000
). Autopsy studies of fatal PPHN demonstrate severe
hypertensive structural remodeling with vessel wall thickening and smooth muscle
hyperplasia even in newborns who die shortly after birth, suggesting that many
cases of severe disease are associated with chronic intrauterine stress. In these
patients, the vascular smooth muscle extends to the level of the intra-acinar arteries,
which does not normally occur until much later in the postnatal period (Haworth
1988
; Murphy et al.
1981
). The severity of vascular remodeling does not allow the
pulmonary vasculature in these infants to appropriately vasodilate in response to
birth-related stimuli, and they will present with profound hypoxemia and clear lung
fields on X-ray, leading many to refer to this as “black-lung” PPHN (Farrow et al.
2005
; Konduri
2004
; Lakshminrusimha and Steinhorn
1999
).
Because idiopathic PPHN is characterized by “pure” vascular disease, it is
probably the best studied of the various causes of neonatal pulmonary hypertension,
and many groups have worked to characterize the underlying fetal and neonatal
pathophysiology that might lead to abnormal remodeling of the fetal and early
neonatal pulmonary vasculature. For instance, a well-known cause of idiopathic
PPHN is constriction of the fetal ductus arteriosus in utero from exposure to
nonsteroidal anti-inflammatory drugs (NSAIDs) during the third trimester
(Manchester et al.
1976
). A fetal lamb model was developed by surgically closing
the ductus in utero, which induces rapid increases in fetal pulmonary artery
pressure, pulmonary vascular remodeling, and a subsequent failure to transition to
extrauterine life (Morin
1989
; Wild et al.
1989
).
Decreased expression and activity of eNOS have been documented in infants
with PPHN, as well as in the ductal-ligation lamb model (Shaul et al.
1997
;
Villanueva et al.
1998
). Increased production of reactive oxygen species (ROS)
by multiple sources leads to vasoconstriction, smooth muscle hypertrophy, and
NOS dysfunction (Brennan et al.
2003
; Konduri et al.
2003
). Further, activity of
vascular sGC is diminished in PPHN lambs (Steinhorn et al.
1995
), and activity of
PDE5 is increased (Hanson et al.
1998b
), both of which lead to decreased cGMP
concentrations (Tzao et al.
2001
).
While prostacyclin appears to be important in the normal pulmonary vascular
transition, much less is known about potential dysregulation of the prostacyclin
pathway in PPHN (Konduri
2004
; Lakshminrusimha et al.
2009a
). Our group has
recently demonstrated decreased expression of the prostacyclin synthase (PGIS)
and the prostacyclin IP receptor in PPHN lambs, leading to reduced vasodilation to
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