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1
Department of Surgical Sciences, Section of Pathology, University of Cagliari, Cagliari, Italy
2
Neonatal Intensive Care Unit, Neonatal Pathology, Puericulture Institute and Neonatal Section, AOU and
University of Cagliari, Cagliari, Italy
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Abstract
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www.jpnim.com Open Access Journal of Pediatric and Neonatal Individualized Medicine vol. 3 n. 2 2014
surfactant, anti-smooth muscle actin and anti- complex lipoprotein composed of 6 phospholipids
CD31 to better evaluate surfactant production, and 4 apoproteins. Surfactant recovered by
pulmonary artery maturation and endothelial cell alveolar wash from most mammals contains 70-
damage, respectively. Finally, the prevalent role of 80% phospholipids, 8-10% protein, and 10%
endothelial dysfunction and endothelial barrier loss neutral lipids, primarily cholesterol. Dipalmitoyl-
is underlined, representing a major pathological phosphatidylcholine (DPPC), or lecithin, is
event in the deposition of HMD. functionally the principle phospholipid. About 1%
of the 10% protein component comprises surfactant
Keywords apoproteins; the remaining proteins are derived
from alveolar exudate. Among the 4 surfactant
Lung, respiratory distress syndrome, hyaline apoproteins identified, surfactant protein B (SP-
membrane disease, surfactant, premature infant. B) and SP-C are 2 small hydrophobic proteins that
make up 2-4% of the surfactant mass. The SP-B
Corresponding author gene is localized on human chromosome 2, and its
primary translation product is 40 kd, which is clipped
Giorgia Locci, Department of Surgical Sciences, Section of Pathology, to become an 8-kd protein in type II cells before
University of Cagliari, Cagliari, Italy; email: giorgettinaloc@gmail.com. entering lamellar bodies to be co-secreted with
phospholipids. The SP-C gene is on chromosome 8;
How to cite its primary translation product, 22 kd, is processed
to an extremely hydrophobic 4-kd protein that is
Locci G, Fanos V, Gerosa C, Faa G. Hyaline membrane disease (HMD): associated with lipids in lamellar bodies. SP-A is
the role of the perinatal pathologist. J Pediatr Neonat Individual Med. an innate host defense, hydrophilic lectin coded
2014;3(2):e030255. doi: 10.7363/030255. on human chromosome 10 that regulates lung
inflammation. SP-A contributes to the biophysical
Introduction properties of surfactant primarily by decreasing
protein-mediated inhibition of surfactant function.
Hyaline membrane disease (HMD), the SP-A facilitates phagocytosis of pathogens by
pathologic correlate of respiratory distress syndrome macrophages and their clearance from the airways.
(RDS) of the newborn, is largely an acute lung SP-D is also a hydrophilic protein of 43 kd that is a
disease of premature infant caused by inadequate collectin with structural similarities to SP-A. SP-D
amounts of surfactant. Decreased surfactant results is a large multimer that is synthesized by type II
in insufficient surface tension in the alveolus alveolar cells and Clara cells, in addition to other
during expiration, leading to atelectasis, decreased epithelial cells in the body. It also binds pathogens
gas exchange, and severe hypoxia and acidosis. and facilitates their clearance. The components
HMD is one of the most common problems seen of pulmonary surfactant are synthesized in the
in premature babies. The more premature the baby, Golgi apparatus of type II alveolar cells [3]. Its
the higher the risk and the more severe the HMD production is regulated by different hormones and
[1]. RDS is the most common respiratory disorder growth factor as glucocorticoids, insulin, prolactin,
of premature newborns and its incidence is directly thyroxine and trasforming growth factor beta
proportional to the degree of prematurity. HMD (TGF-). Its production generally starts around the
typically worsens over the first 48 to 72 hours and 24th to the 28th week of pregnancy, and surfactant is
then improves with treatment. More than 90 percent found in amniotic fluid between 28 and 32 weeks.
of babies with HMD survive. The incidence and By about 35 weeks of gestation, most babies
severity of HMD are inversely proportional to have developed adequate amounts of surfactant.
gestational age and birth weight, ranging from 5% Surfactant deficiency may not be the sole cause
at 36 weeks up to 65% at 29 weeks of gestation [2]. of hyaline membrane formation. An early
HMD predominantly occurs in infants younger than morphological feature of HMD is necrosis of the
32 weeks gestation and weighing less than 1,200 g. bronchiolar epithelium. This has been attributed to
pulmonary circulatory problems and may explain
Surfactant formation and physiology the development of hyaline membranes in some
full-term infants with abruption placentae, placenta
HMD is a disorder related primarily to previa and fetal malposition, as well as their
deficiency of pulmonary surfactant. Surfactant is a occurrence in some stillborn infants [4].
Caucasian or male newborns (M:F = 2:1); delivery, particularly when done before labor
previous birth of newborns with HMD; [8]. Another study, comparing of singleton and
cesarean delivery; multiple-birth outcomes of infants born before 32
perinatal asphyxia (lack of air immediately weeks of gestation showed a higher incidence of
before, during or after birth); RDS among multiple-birth infants [9]. Infants born
cold stress (a condition that suppresses surfactant to mothers with glucose intolerance (diabetic) are
production); at increased risk of morbidity and mortality related
perinatal infection and growth retardation; to respiratory distress. Surfactant-associated
babies with patent ductus arteriosus; protein of Mr 28,000 to 35,000 (SAP-35) is an
multiple births (multiple birth babies are often abundant glycoprotein present in the alveolus of
premature); the lung, which controls the structural organization
infants of diabetic mothers; of surfactant phospholipids regulating secretion
maternal hypothyroidism; and metabolism. Glucocorticoids both enhance
mutations in the genes encoding the surfactant and inhibit SAP-35 expression in fetal lung
proteins [7]. explants. We know that fetal hyperinsulinemia and
Cesarean delivery has been show to represent hyperglycemia, or both, inhibit the morphologic
an independent risk factor for RDS, the incidence differentiation of type II epithelial cells in
of HMD being reduced with labor before cesarean, association with decreased phospholipid surfactant
but still elevated. This supports the importance of synthesis or secretion. Insulin is also a potent
being certain of fetal lung maturity before cesarean inhibitor of SAP-35 expression in fetal lung tissue,
Figure 3. Pathogenesis of hyaline membrane disease (HMD). Vascular disruption causes leakage of plasma into the
alveolar spaces and layering of fibrin and necrotic cells arise from type II pneumocytes (hyaline membranes) along the
surface of alveolar ducts and respiratory bronchioles partially denuded of their normal cell lining.
and decreased SAP-35 was previously observed Pathological features in hyaline membrane
in amniotic fluid of women with diabetes during disease
pregnancy. Recent progress in the management
of diabetes in pregnancy, characterized by more Grossly, the lungs are reduced in volume and
rigorous metabolic control, has decreased the show a solid or liver-like consistency. The
risk of RDS for the infant of the diabetic mother neonatal lungs appear congested, with marked
and is associated with normal levels of SAP-35 atelectasis [14].
in amniotic fluid [10]. An association between The most important histological features are
maternal hypothyroidism and the risk of RDS in presented below (Fig. 4):
newborns has been described. Thyroid hormones a. dilated terminal and respiratory bronchioles
are very important for the development of the fetus, and alveolar ducts lined by acellular eosino-
and especially for the production of lung surfactant. philic hyaline membranes are observed;
Recent studies have shown that newborns of b. the membranes are composed of necrotic
hypothyroid mothers need of intensive care after alveolar lining cells, amniotic fluid constituents
birth, especially due to complications such as and fibrin [15];
premature birth, low birth weight and increased c. the membranes form as early as 2-3
neonatal respiratory distress [11]. Moreover, hours after the insurgence of RDS. They
associations with genetic disorders have been are well formed by 8-12 hours; in the absence
noted. The available studies mainly concentrate on of high oxygen tensions and mechani-
surfactant proteins (SP-A, SP-B); mutations in the cal ventilation, resolution by 24-48 hours
genes enconding SP-B, SP-C and the phospholipid occurs;
transporter are associated with respiratory distress d. membranes can be stained bright yellow
and interstitial lung disease in the pediatric in infants with kernicterus, in the setting
population [12]. Hereditary SP-B deficiency is the of unconjugated bilirubin, intraventricular
most frequent genetic condition associated with hemorrhage, intrahepatic bile stasis, and
HMD [13]. disseminated intravascular coagulation [4];
A. B.
C. D.
Figure 4. A, B. Preterm human lung: hyaline membrane disease (HMD) are shown (arrows). Hematoxylin-eosin (HE).
OMx200. C, D. Preterm human lung: HMD are shown (arrows). HE. OMx400.
Although characteristic of HMD, hyaline The first approach to the histological study of a
membranes are a nonspecific finding with a neonatal lung should include the evaluation of lung
number of causes, which should be considered development. In order to give the clinician useful
especially in the term and post-term infant with data regarding the ability of the newborn lung
RDS. Hyaline membranes can be seen associated to function in the extrauterine environment, the
with meconium aspiration, neonatal pneumonia, following features should be reported:
pulmonary edema and hemorrhage and with a. the degree of alveolarization of saccular structures;
various irritants to the terminal airways and b. the presence of reticulin fibers, tipically diffuse
alveoli. in the immature lung;
c. the presence of elastic fibers, typical of lung
Discussion maturation;
d. the differentiation of alveolar ephitelium, with
The finding of hyaline membranes at the the evolution from cuboidal undifferentiated
histological examination of lungs is a frequent progenitor cells to type I pneumocytes;
event in preterm newborns died in the clinical e. the degree of maturation of the pulmonary
setting of RDS. Even though hyaline membranes arterial wall and in particular the persistence of
should not be considered specific, on the other fetal arteries, characterized by a narrow lumen
hand they are characteristic of HMD and, in the and a thick muscular wall;
majority of cases, allow to confirm the clinical f. the differentiation of the alveolar cells
diagnosis. responsible for surfactant production. To this
The role of the pathologist should not be end, immunohistochemistry against surfactant
restricted to description of the presence of protein-A and B is mandatory.
hyaline membranes in the neonatal lung: other
pathological data may be important for reaching Vascular changes
a complete clinical-pathological diagnosis. The
most important histological features required in After the evaluation of the architectural
these cases are here reported. changes, the pathologist should focus on the most