LUNG DEVELOPMENT
While the development of conductive airways is complete at birth, the
lungs undergo a prolonged period of postnatal development and
maturation. Lung development is characterized by four phases (five when
considering the embryonic period during which the respiratory
tract rises from the foregut at approximately 3-5 weeks gestation)
(Figure 4) (35, 44). In the first stage of lung development, the
so-called “pseudoglandular phase ”, occurring at 5-16 weeks of
gestation, the pre-acinar branching and primitive capillary plexus begin
to develop, and the mesenchyme is abundant. At the end of this stage,
the bronchial tree is fully developed (45, 46). The “canalicular
phase ” occurs from the 17th to the 27th week of gestation and is
characterized by the development of acini with primitive alveoli. In
this phase, type I and type II pneumocytes start to differentiate so
that they can be recognized after 24 weeks of gestation (35). Moreover,
an increase in capillarization, which also becomes closer to the airway
surface epithelium, as well as a decrease in the amount of connective
tissue, have been described, indicating the start of the development of
the alveolar-capillary barrier. The “saccular phas e” starts at
28-36 weeks of gestation and continues until birth: during this phase,
type II pneumocytes start to produce surfactant, saccules develop, and
respiratory units differentiate. This phase is crucial: as a matter of
fact, babies born before 36 weeks may show respiratory distress
requiring the administration of exogenous surfactant, the severity of
which is related to the degree of prematurity (46). Even if true alveoli
begin to appear around the 28th week of gestation, the last phase, the
“alveolar phase ”, starts conventionally at 37 weeks, since
alveolarization occurs mainly after birth (33, 47, 48). In fact, at
birth, neonates have from 17 to 71 million alveoli, whereas adults have
200-600 million, so 85% of alveoli are added postnatally (35, 49). In
particular, it has been reported that the volume of the lung doubles by
6 months of life, triples by 1 year (50) and increases by a factor of
approximately 13 between the ages of 1 month and 7 years (35). The
growth of the airways occurs more slowly than that of parenchyma,
particularly in the first year of life, and this disproportionate growth
pattern has been defined as “dysanaptic growth ” (48, 51). The
alveolarization process is still not completely understood (52);
nevertheless, the prevailing hypothesis is that alveoli stop multiplying
by 2-3 years of age and then undergo a process of increase in volume and
surface area (47, 53, 54), even if some authors have suggested that
alveoli formation may continue until 7-8 years of age (55-58). A recent
study by Narayanan et al. contradicts these hypotheses: in their study,
alveolar dimensions were noninvasively assessed in subjects between 7
and 21 years of age by measuring self-diffusion of hyperpolarized
helium-3 in the lung periphery during a brief breath-hold using MR (59).
The results of the study show that alveolar size does not increase, and
thus, the described 3- to 4-fold increase in lung volume between 7 years
and adulthood (60) could only be explained by neo-alveolarization
through childhood and adolescence. This finding could be noteworthy
considering the chances of recovery for children having suffered early
lung damage due to respiratory diseases as well as several detrimental
environmental factors (51, 52). Regarding differences between sexes, it
should be noted that boys have more alveoli but the same mean alveolar
size as females; therefore, they have larger lungs at any given age.
Males also have more respiratory bronchioles than females, since the
number of alveoli supplied from one respiratory bronchiole is the same
in boys and girls (61). These differences may be caused by the
influence of sex hormones on lung development, especially in
adolescence, when remarkable changes also occur to the thoracic cage in
terms of anatomy and muscle power (35, 46). Last but not least, it
should be noted that even if children have fewer alveoli, their
air-blood contact surface ratio is 1 m2/kg, which is
almost the same as that in adults. Nonetheless, infants lack
interalveolar pores of Kohn (62), bronchiolar-alveolar channels of
Lambert (63) and interbronchiolar channels of Martin (64), which are
compensatory structures linking alveoli with each other, alveoli to
bronchioles, or bronchioles to each other, respectively, to facilitate
collateral ventilation overcoming distal obstructions (Figure 3) (65,
66). The development of these structures is usually complete by the 12th
month of life (52, 67-69).