According to Jobe [
11], “the injury resulting in BPD likely begins as altered lung development before delivery in many infants and can be initiated by resuscitation at birth and then amplified by postnatal exposures”. The timing, type and duration of exposures, together with the genetic characteristics of the child, influence the pattern of lung damage that can occur. BPD as initially described (i.e., old BPD) was considered the result of an aggressive mechanical ventilator approach in terms of peak pressures and oxygen concentrations on a relatively mature lung lacking surfactant (i.e., ≥ 32 weeks of gestation) [
12]. Several experimental studies have clearly shown that ventilation with high positive pressure and excess volume can lead to alveolar damage and severe local inflammation, with higher than normal tumour necrosis factor-α, interleukin (IL)-1β, interleukin-6, and macrophage inflammatory protein-2 concentrations in the lung [
13,
14]. Moreover, aggressive ventilation has been associated with reactive oxygen species (ROS) production. Maturation of antioxidant enzyme capacities is gradual during foetal life, and some enzymes, such as catalase and copper–zinc superoxide dismutase, are significantly induced by breathing air after birth [
15], indicating that even a slight increase in reactive oxygen species in moderately preterm babies can lead to lung damage [
12‐
14]. Moreover, in experimental animals, supraphysiological oxygen concentrations during the first days of life were found to be able to compromise alveolarization and lead to right ventricular hypertrophy, vascular remodelling, and the development of small airways disease, smooth-muscle hypertrophy, and oxidative stress [
16]. Similar findings were shown in lung tissue sections of neonates born before term who developed respiratory distress syndrome and were treated with high oxygen concentrations and aggressive ventilation [
17].
Thanks to improvements in neonatal intensive care, both the pathogenesis and the histology of BPD have changed, and a new type of BPD has developed. More preterm infants born in the early stages of lung development presently suffer from BPD, with a frequency inversely correlated with gestational age. Most cases of BPD occur in babies born before the 32nd week of gestation, when the lung is in the canalicular (from the 17th to 26th week of gestation) or saccular (from the 27th to 36th week of gestation) stage of development [
17]. Particularly in EPT, the lung structure is very immature. The respiratory bronchioles, precapillaries and mucous glands in the bronchi are not completely developed, the interstitium has not thinned adequately to form the blood–air barrier, and surfactant production by the lung epithelial cells has not started. Moreover, when preventive and therapeutic measures, such as antenatal steroid and postnatal surfactant administration, are used, even subjects born several weeks before term often develop mild to moderate respiratory problems. Unfortunately, several factors can interrupt lung development, reducing pulmonary microvascular growth and alveolarization. Practically, when foetal or postnatal factors, together with genetic predisposition, interact with a lung in early development, the development is altered, and a new type of BPD (i.e., new BPD) occurs. The already cited mechanical trauma and oxygen toxicity again play roles, but several different exposures, both prenatal and/or postnatal, are involved in this altered lung development. Maternal smoking and hypertension have been found to be associated with a twofold increase in the odds of developing new BPD [
18]. Infections can have similar effects, although results of the studies specifically planned in this regard were in some cases partly conflicting. The relationship seems well defined for postnatal infections. Lapcharoensap et al., in a retrospective, population-based cohort study, examined whether reductions in rates of nosocomial infection were associated with changes in rates of BPD [
19]. Adjusted rates of nosocomial infections and BPD from a baseline period (2006–2010) were compared with a later period (2011–2013). A total of 22,967 infants were included in the study. From the first to second period, the incidence of nosocomial infections decreased from 24.7 to 15%, and BPD decreased from 35 to 30%. Adjusted hospital rates of BPD and nosocomial infections were correlated positively with a calculated 8% reduction in BPD rates attributable to reductions in nosocomial infections. Similar findings were reported when the role of sepsis was considered [
20]. More controversy, however, exists regarding the relevance of chorioamnionitis. In a meta-analysis of 57 studies enrolling more than 15,000 subjects, it was found that, considering together all the cases of chorioamnionitis regardless of type, infants born to mothers with this condition had a risk of developing BPD only slightly higher than that of controls (weighted mean differences [WMD] 1.89; 95% confidence interval [CI] 1.5–2.3). The association remained significant for histological (WMD 2.19; 95% CI 1.7–2.7) but not for other types of chorioamnionitis. Moreover, the conclusion of the meta-analysis was considered highly debatable mainly because most of the included studies had poor methodological quality [
21]. However, a recent retrospective cohort study, in which it was evaluated whether chorioamnionitis affected the incidence of BPD after accounting for the increased risk of death, showed that prenatal infection was significantly associated with BPD and perinatal death (odds ratio [OR] 5.18; 95% CI 4.39–6.11] [
22]. A role also seemed to be played by growth restriction. Neonates small for their gestational age were found to have a more than a two times higher risk (OR 2.73; 95% CI 2.11–3.55) of BPD development than subjects with weight appropriate for their gestational age [
23]. Moreover, poor nutrition in the first days of life has been found to be associated with an increased risk of BPD [
24]. Finally, genetics might contribute to BPD development. In a study conducted in twins [
25], it was shown that, among monozygotic twin pairs, the observed concordance for BPD was significantly higher than the expected concordance. After controlling for covariates, genetic factors accounted for 53% of the variance in predisposition to BPD. Moreover, it was reported that the
SPOCK2 gene might be considered a new possible candidate susceptibility gene for BPD because its lung expression pattern points towards a potential role in alveolarization [
26]. However, the role of genetics requires further evaluation. A large genome-wide association study enrolling more than 1700 neonates did not identify genomic loci or pathways that could account for the previously described heritability of BPD [
27].