The first stage is the embryonic, which spans from 3 to 6 weeks postconception. In this phase, the lung starts developing at around day 26 of gestation as a ventral outpouching of the foregut (Fig. 9.1). This ventral diverticulum (lung bud) will start forming the trachea and the two bronchial buds that will give rise to the left and right bronchi. The asymmetry of the main bronchi is already established at this stage: the left bud is smaller and directed laterally and the larger right bud is directed more caudally [18]. Toward the end of the embryonic stage, the bronchial buds undergo subsequent divisions, resulting in the precursor structures of the pulmonary lobes, three on the right and two on the left (Fig. 9.1), and a small pulmonary circulatory system starts developing [19, 20]. At this point, no sex differences are observed in lung development.

The embryonic stage is followed by the pseudoglandular stage that extends from 6 to 16 weeks of gestation and that is characterized by bronchial development and airway branching. In this stage, the bronchial tree is developed up to the terminal bronchiole, and the respiratory parenchyma and respiratory ducts are formed, together with a primitive pulmonary circulatory system [21, 22]. Lung epithelial cells begin to differentiate into precursors for bronchial smooth muscle, cartilage, and submucosal glands in a process highly dependent on epithelial and mesenchymal interactions [21, 23]. The bronchial tree is initially coated by a cubic epithelium, which is the precursor of the ciliated epithelium, and by secretory cells and immature type II cells. In this stage, sex differences begin to appear in fetal mouth movement, an indication of fetal lung maturation, showing advanced breathing in females more than in males [24].

The next stage is the canalicular phase , starting at week 16, and extending until week 26 of gestation. In this period, the basic gas-exchanging airway units are formed by further subdivisions of the distal airways (Fig. 9.1). These canaliculi are formed by branching of the terminal bronchioles, and compose the now respiratory parenchyma. The groups of air spaces that are formed from a single respiratory bronchiole form an acinus. Vascularization of the peripheral mesenchymal tissue is the foundation for the later exchange of gases at these respiratory units. The lumen of these becomes wider and the epithelial type II cells begin to secrete surfactant, and differentiate into type I cells [22]. Capillaries move into close contact with the surface epithelium, and connective tissue is reduced. The first functional sex differences are noticed at this stage, and these are attributed to hormonal influences, as well as sex differences in gene expression. At around 16 weeks of gestation, the lungs of female fetuses are usually more mature than those of males, and begin to produce surfactant lipids [5, 10, 25, 26] (Fig. 9.1).

At the end of the canalicular phase, and the beginning of the saccular phase, spanning from weeks 26–36 postconception, a large part of the amniotic fluid is produced by the lung epithelium. At this stage, lung maturity can be measured clinically by quantifying lipid content in the amniotic fluid (ratio of lecithin to sphingomyelin), based on the production of surfactant by type II cells [27]. As indicated, female fetuses usually show a more mature phospholipid profile at this stage, which correlates with an earlier production of surfactant components [25].

During the saccular phase , drastic changes occur in the morphology of the developing lung. Further subdivisions at the terminal bronchioles give rise to clusters of sacs that will later become the alveoli (Fig. 9.1). These sacculi are internally coated with type I and type II cells and the parenchyma between them contains primary septa that are composed of networks of capillaries. These contain small protrusions that will later become alveoli via delimitation by secondary septa. At the end of the saccular phase, all generations of the conducting and respiratory branches are generated, and about 1/3 of the roughly 300 million alveoli are fully developed.

The saccular phase is characterized by type II cell maturation and surfactant production, which are promoted by paracrine communications with cells of the interstitial space. Pulmonary surfactant is a lipoprotein complex (90 % lipids, 10 % proteins), responsible for preventing alveolar collapse at low lung volumes. By decreasing surface tension at the alveolus, lung surfactant promotes gas exchange and lung mechanics. Pulmonary surfactant also enhances lung innate immunity by the actions of surfactant proteins A and D (collectins). Thus, in preterm infants born at less than 30 weeks of gestational age, surfactant deficiency greatly contributes to the development of RDS, and related morbidities such as BPD, patent ductus arteriosus, arterial pulmonary hypertension, and long-term neurological disabilities [12, 28, 29]. Surfactant synthesis and secretion significantly increase after week 30 in preparation for the transition to air breathing, and the male lung begins to synthesize surfactant later in gestation than the female lung (Fig. 9.1). This delay has been attributed to androgens and other factors, as described later in the chapter [6]. Therefore, female newborns have increased airflow rates, but lower airway resistance compared with male newborns, and they are less likely to develop RDS [11, 30].

Lastly, at the postnatal alveolar stage , starting at birth (36 weeks postconception) and extending throughout adolescence, the number of alveoli largely increases [1]. This alveolar multiplication process (alveolarization) is very active within the first 2 years of life, although the alveolar size and number of alveoli per unit area does not change much during this period. The respiratory epithelium differentiates into a variety of cell types including ciliated, goblet, basal, and Clara cells [31]. Although maturation appears to be more advanced in female fetuses than in male fetuses, girls on average have smaller lungs and fewer respiratory bronchioles than boys at birth. Female neonates also have higher size-corrected flow rates, specific airway conductance, and a higher ratio of large airways to small airways than males, and it has been suggested that boys have more respiratory bronchioles per lung volume than girls [2, 32]. Furthermore, the growth of airways is slower than the growth of lung parenchyma in boys, whereas in girls the growth of airways is proportional to the growth of parenchyma. This “dysynaptic” growth originates in early childhood, and remains constant during growth [1, 33]. Boys in general have bigger lungs than girls of the same stature, and studies have suggested that boys have more respiratory bronchioles than girls, but no sex differences have been reported in alveolar dimensions, and in number of alveoli per unit area. In terms of lung function, studies in teenagers showed that growth in forced expiratory volume in 1 s (FEV1) increases with age, reaching a peak at ages 12–13 in girls and at age 14 in boys [34, 35]. The FEV1 was shown to increase until the age of 17 in both sexes, but the continued growth in lung function after attainment of full height is higher in boys than in girls [36]. Finally, in adult life, sex differences have also been documented in lung structure and morphology [8, 33, 37, 38]. Height-matched men have larger diameter airways, total number of alveoli, and larger lung volumes and diffusion surfaces compared with women. However, for a given lung size, women have larger airways size than men [38].

In summary, given the gender effects on lung structure and function during lung development (Table 9.1), males are at higher risk for newborn and early childhood lung complications. In postnatal and adult life, however, the lower lung capacity in females, and the influence of sex hormones, makes women more prone to the damaging effects of air pollution and pulmonary limitations during exercise [39, 40]. Additionally, by modulating circulating levels of estradiol and progesterone, the menstrual cycle can also affect pulmonary function and inflammatory lung disease outcomes in women [41–43].