Bronchopulmonary dysplasia (BPD) was first described in 1967 by Northway et al., who hypothesized that its pathogenesis stemmed from prolonged mechanical ventilation of the surfactant-deficient lung with high concentrations of inspired oxygen (hyperoxia) . Since then, new therapies and advances in ventilatory management have led to the disappearance of the “classic” or “old” BPD lesions described in that landmark study. In the present era, BPD most often affects only extremely premature infants born between 23 and 28 weeks gestation . This “left-shift” in the gestational age of the affected population, during which time critical events in lung development are occurring, has required a profound change in our investigation and understanding of both the histopathology and pathophysiology of BPD.
The developing human lung undergoes a well-described series of morphologic changes, each of which occurs within a discrete period of embryonic and fetal development. It is not until the saccular stage, which begins at 24–26 weeks gestation, that pulmonary alveoli begin to form . The lung of an extremely premature neonate consists of abnormal interstitium, an epithelium with few alveoli-forming secondary crests, an immature pattern of elastin deposition and an incompletely developed vasculature. Interestingly, these histological findings persist in the lungs of neonates who require long-term mechanical ventilation after delivery at an extremely premature gestational age. This so-called arrest of alveolar development defines the modern-day or “new” BPD .
Currently little is known about the molecular and cellular basis of BPD [2, 4, 5]. This may be due, in part, to the complexity and prohibitive expense of traditional animal models of newborn lung injury, such as prolonged mechanical ventilation of premature baboons or lambs [4, 6]. In this regard, the murine hyperoxia model may provide an ideal alternative to study the pathologic arrest of alveolar development in BPD. Recent research has shown that exposing newborn mice to high concentrations of ambient oxygen recapitulates the histopathology of BPD [7–9]. This is an important finding, as the lungs of mice born naturally at term have reached the same developmental stage as those of the extremely premature human neonate [7, 10]. Furthermore, current technologies have greatly facilitated generation and availability of genetically engineered mouse strains that will allow dissection of molecular pathways in BPD.
Alveolar development is a complex process involving multiple mechanisms relating to cell cycle, cell adhesion, mobility and taxis, and angiogenesis. Recent work by our group has demonstrated the dynamic regulation of microRNAs (miRNAs) during lung organogenesis . MiRNAs are a class of small non-coding RNA that regulate gene expression either by inhibiting protein translation or by cleavage of mRNA targets based on the pairing of miRNAs and their mRNA target binding sites . Individual miRNA may target multiple mRNAs, and individual mRNA may contain sequences complementary to multiple miRNA family members [13, 14]. It is estimated that miRNAs may be responsible for regulating the expression of nearly one-third of the human genome . MiRNAs are known to play multiple roles in organ development, carcinogenesis, and immune responses [16, 17], and have been implicated in many critical cellular processes, including apoptosis, proliferation, and differentiation . Despite the identification of more than 800 mature human miRNAs and 700 mouse miRNAs, much remains to be discovered about their functional targets and biologic role.
In the current study, we explored the regulation of miRNAs and corresponding target mRNAs during the arrest of alveolar development prominent in a murine model of BPD. We provide evidence that dynamic regulation of miRNAs may play a prominent role in the pathophysiology of BPD.