and endocytosis in alveolar type II cells. Thus, the type II
cells are involved in both the synthesis and the recycling
of surfactant.
The phospholipids are mainly synthesized starting from
glycerol 3-phosphate which is derived from glucose. The
CDP-choline pathway is utilized in the synthesis of phos-
phatidylcholine or lecithin (Figure 19-2). The protein com-
ponent of surfactant is lung-specific and consists of four
proteins designated SP-A, SP-B, SP-C, and SP-D. These
surfactant proteins perform important functions that lead
to a reduction in alveolar surface tension during respira-
tion. These include structural transformation of lamellar
body to tubular myelin (SP-A and SP-B in the presence
of Ca2+), enhancement of surface-tension lowering prop-
erties and promotion of adsorption of surfactant phospho-
lipids at the air-liquid interface (SP-B and SP-C), reuptake
by endocytosis of surfactant by type II cells, and the activa-
tion of alveolar macrophages to facilitate surfactant clear-
ance. Both SP-A and SP-D possess antimicrobial proper-
ties. SP-A is chemotactic for macrophages and promotes
bacterial phagocytosis.
The most abundant surfactant protein is a water-soluble
asialoglycoprotein that is a multimer consisting of six
triple helical structures. The primary structure of SP-A
is highly conserved among several species. It has two do-
mains; the N terminus is collagen-like with Gly-X-Y re-
peats (where Y is frequently a prolyl residue), and the
C terminus has lectin-like properties. SP-B and SP-C are
highly hydrophobic proteins. SP-D is a glycoprotein and
has a structure similar to SP-A. The importance of one sur-
factant protein is demonstrated in neonates who are born
with an inherited deficiency of SP-B. Infants with a SP-B
deficiency require ventilatory support and extracorporeal
membrane oxygenation. However, almost all die during
the first year of life due to progressive respiratory fail-
ure. Lung transplantation is the only therapy by which the
SP-B-deficient infants can be saved from death.
Surfactant biosynthesis is developmentally regulated.
The capacity for the fetal lung to synthesize surfactant
occurs relatively late in gestation. Although the type II
cells are identifiable at
2 0 - 2 2
weeks of gestation, the se-
cretion of surfactant into the amniotic fluid occurs during
30-32 weeks of gestation. Thus, for the infant a conse-
quence of prematurity is
respiratory distress syndrom e
(RDS), which is a leading cause of neonatal morbidity
and mortality in developed countries. The synthesis of
surfactants is regulated by factors that include glucocorti-
coids, thyroid hormones, prolactin, estrogens, androgens,
catecholamine (functioning through /3-adrenergic recep-
tors and cAMP), growth factors, and cytokines. Gluco-
corticoids stimulate lung maturation, thus glucocorticoid
therapy in women in preterm labor prior to 34 weeks of
408
gestation can significantly decrease the incidence of RDS
in the premature neonates.
Thyroid hormones also accelerate fetal lung matura-
tion. Fetal thyroid hormone levels may be increased by
antenatal administration of thyrotropin-releasing hormone
(TRH), a tripeptide that crosses the placental barrier, stim-
ulates fetal pituitary production of thyroid stimulating hor-
mone (TSH), and which, in turn, increases fetal thyroid
hormone production (Chapter 33). This indirect method of
enhancement of fetal thyroid hormone production is uti-
lized because thyroid hormones do not readily cross the
placental barrier. Insulin delays surfactant synthesis and so
fetal hyperinsulinemia in diabetic mothers may increase
the incidence of RDS even in the full-term infant. Andro-
gen synthesized in the fetal testis is the probable cause of
a slower onset of surfactant production in male fetuses.
Prophylactic, or after onset of RDS, administration of
synthetic or natural pulmonary surfactants intratracheally
to preterm infants improves oxygenation and decreases
pulmonary morbidity.
In adults, a severe form of lung injury can develop in as-
sociation with sepsis, pneumonia, and injury to the lungs
due to trauma or surgery. This catastrophic disorder is
known as
acu te respiratory d istress syndrom e
(ARDS) and
has a mortality rate of more than 40%. In ARDS, one of the
major problems is a massive influx of activated neurophils
which damage both vascular endothelium and alveolar
epithelium and result in massive pulmonary edema and
impairment of surfactant function. Neutrophil proteinases
(e.g., elastase) break down surfactant proteins. A poten-
tial therapeutic strategy in ARDS involves administration
of both surfactant and antiproteinases (e.g., recombinant
a i-antitrypsin).
Biochemical Determinants of Fetal Lung Maturity
The need for surfactant production does not become es-
sential until birth because no air liquid interface exists
in the alveoli
in utero,
and fetal oxygen needs are met
by maternal circulation. The pulmonary system, includ-
ing surfactant production, is among the last of the fetal
organ systems to attain functional maturity. Since preterm
birth is associated with significant neonatal morbidity and
mortality in inadequate oxygen supply to an immature pul-
monary lung system, the assessment of antenatal fetal lung
maturity is necessary to develop a therapeutic strategy in
the management of a preterm infant. The biochemical de-
terminants are measured primarily in the amniotic fluid
obtained by amniocentesis.
In a normal pregnancy, the lung is adequately developed
by about the 36th or 37th week. Biochemical changes
occurring during this period of gestation can be used to
chapter 19
Lipids II: Phospholipids, Glycosphingolipids, and Cholesterol
