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).