The respiratory system undergoes significant growth and development during the third trimester of fetal life and throughout the first year of infancy. Postnatally, the pattern of physiological airway development is best characterized by the global lung initiative (http://​www.​lungfunction.​org/​). In healthy children, lung volume and function (FVC and FEV₁) continue to increase throughout childhood and reach a plateau at 20 to 25 years [38]. Subsequently, lung volume and function decline steadily with age. In individuals who experienced early lung injury or maldevelopment during infancy, a reduction in peak lung growth may appear [8]. The outcome of poor lung development depends on the type and severity of the insult as well as the developmental stage of the lung at the time it occurred [39]. Longitudinal studies show temporal tracking of small airway diseases among preterm-born individuals [40, 41].

The “new” BPD is often described with pathologic changes of large, simplified alveolar structures, a dysmorphic capillary configuration, and variable interstitial cellularity and/or fibroproliferation [15]. Airway and vascular lesions, when present, tend to be present in infants who develop more severe diseases over time [42]. The concept that “new” BPD results in an arrest in alveolization should be modified to that of an impairment in alveolarization since evidence shows that short ventilatory times and/or the use of nCPAP allow continued alveolar formation [42]. An area of emerging interest in the field of lung imaging is 3He diffusion MRI. With this technique, alveolar damage was studied in survivors of extreme preterm birth by comparing alveolar dimensions between full-term born and preterm-born school children [43]. Alveolar size at school age was similar in survivors of extreme prematurity and full-term born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for this finding is catch-up alveolarization.

Therefore, prematurity per se may have an impact on lung growth, but neonatal events and treatment, for example, supplemental oxygen or mechanical ventilation, may cause inflammatory responses followed by a repair process. The repair process may be “healing” but may also become chronic in response to continued inflammation, resulting in structural changes in the airways that are referred to as remodeling. These structural changes may result in irreversible narrowing of the airways. Over time, in most children, with or without BPD, pulmonary function improves. Whether this improvement represents repair of damaged lung tissue or growth of new lung tissue, or both, has yet to be determined.

Children and adolescents with severe BPD, however, show evidence of chronic obstructive pulmonary disease. Kotecha et al. systematically reviewed the literature to determine whether the percentage predicted forced expiratory volume during 1 s (%FEV₁) is lower in preterm-born subjects, with or without BPD, in comparison to full-term born controls. They found that %FEV₁ is decreased in preterm-born survivors, even in individuals who did not develop BPD. For the preterm-born group without BPD, the mean difference %FEV₁ in comparison to full-term born controls is −7.2 %, and for the BPD groups, it was −16.2 % to −18.9 %, respectively (according to the definition of BPD) [44].

Former preterm-born children show little evidence of eosinophilic inflammation [45]. Exhaled nitric oxide concentrations are significantly lower in BPD survivors than in asthmatic cases, suggesting that different pathogenetic mechanisms characterize these two chronic obstructive lung diseases [46].

When inflammation plays a role, treatment with inhaled corticosteroids might be effective. A recent systematic review studied whether inhaled bronchodilators and inhaled corticosteroids improve long-term outcomes in neonates with BPD. No meta-analysis was attempted due to the large degree of heterogeneity and quality assessment of the studies included. The conclusion was that although these inhaled therapies seem to have some benefit, very limited data are available suggesting that these treatments at neonatal age improve long-term outcomes of infants with BPD [47].

Kotecha et al. systematically reviewed the evidence for bronchodilator treatment in former preterm-born children and adults. They concluded that the majority of the studies reported short-term effects of a single-dose administration with an improvement in %FEV₁ after bronchodilator treatment. There is, however, a paucity of data on the effect of longer term administration of bronchodilators on the lung function of former preterm-born children [48]. The number of studies with inhaled corticosteroids is small in older preterm-born children and these studies show no effect [49]. There is no current evidence to advocate widespread use of bronchodilators or inhaled corticosteroids, even though a component of variable airflow obstruction may be present. Additional evidence for optimal treatment is required [50].

Acute inflammation due to respiratory tract infections, such as respiratory syncytial virus (RSV) infection, could be an important mechanism of recurrent wheeze during the first year of life in preterm-born infants [51]. A connection between viral infections and exaggerated cell death and inflammatory pathways in the developing lung was recently revealed [52].

In contrast to early lung development, a process exemplified by the branching of the developing airways, the later development of the immature lung remains poorly understood. A key event in late lung development is secondary septation, in which secondary septa arise from primary septa, creating a greater number of alveoli of a smaller size. This phase in lung development dramatically expands the surface area over which gas exchange can take place [52]. Secondary septation, together with architectural changes to the vascular structure of the lung that minimize the distance between inspired air and blood, is the objective of late lung development. When late lung development is disturbed, lung architecture is malformed. Depending on the severity of the architectural malformation, there may be serious consequences in terms of respiratory function, as well as long-term consequences in later life [52]. It is not clear whether early preterm lung injury is associated with structural damage to surrounding lung tissue because it is difficult to obtain histological tissue for study purposes. Nevertheless, a crucial mechanism that secures airway patency and thus adequate maintenance of functional residual capacity (FRC) is airway tethering [53–55]. Tethering is the element that couples lung volume to airway patency. Thus, as lung volumes increase, airway diameter and hence expiratory flows increase. Maturation of the alveolar network improves parenchymal elastance and, as a consequence, airway tethering. Immaturity adds up to the elements constituting the vulnerability of preterm infants [53].

Radiologic studies in older and more severe cases with BPD showed structural changes such as emphysema on high-resolution CT scans [33, 56, 57]. There seems to be an association between the extent of radiological abnormality on high-resolution CT scans and the severity of lung function impairment [33].