Aberrant signaling pathways of the lung mesenchyme and their contributions to the pathogenesis of bronchopulmonary dysplasia

Abstract

Bronchopulmonary Dysplasia (BPD) is a chronic lung disease in infants born extremely preterm, typically before 28 weeks gestation, characterized by a prolonged need for supplemental oxygen or positive pressure ventilation beyond 36 weeks postmenstrual age. The limited number of autopsy samples available from infants with BPD in the post-surfactant era has revealed a reduced capacity for gas exchange resulting from simplification of the distal lung structure with fewer, larger alveoli due to a failure of normal lung alveolar septation and pulmonary microvascular development. While the mechanisms responsible for alveolar simplification in BPD have not been fully elucidated, mounting evidence suggests that aberrations in the cross-talk between growth factors of the lung mesenchyme and distal airspace epithelium play a key role. Animal models that recapitulate the human condition have expanded our knowledge of the pathology of BPD and have identified candidate matrix components and growth factors in the developing lung that are disrupted by conditions that predispose infants to BPD and interfere with normal vascular and alveolar morphogenesis. This review will focus on the deviations from normal lung development that define the pathophysiology of BPD and summarize the various candidate mesenchymal-associated proteins and growth factors that have been identified as being disrupted in animal models of BPD. Finally, future areas of research to identify novel targets affected in arrested lung development and recovery will be discussed.

Thrown off balance: the effect of antenatal inflammation on the developing lung and immune system

“…45,46 Despite these developmental advantages of large animals over rodents, rodent models offer the possibility to use transgenic approaches to study candidate genes in the pathogenesis of IA inflammation/infection. 35,[47][48][49] Therefore, both animal models are useful to study the effects of intraamniotic infection/inflammation on lung development. In future large animal research, conditional overexpression or knockdown of candidate genes affected by IA inflammation/infection would allow a more accurate identification of genes leading to morbidity in preterm infants.…”

“…77 Conversely, how these lung developmental pathways are affected by IA inflammation is still poorly understood. 35,78 BPD is characterized by a disruption of lung alveolarization and vascularization, leading to fewer but larger alveoli and a simplified vascular structure. 54,55 Several aberrant and interacting signaling pathways of the lung mesenchyme contribute to BPD development.…”

“…54,55 Several aberrant and interacting signaling pathways of the lung mesenchyme contribute to BPD development. 35 IA inflammation can spread to the fetal lung, leading to lung injury and remodeling. 70,79,80 In fetal sheep this resulted in persistent structural changes in the fetal lung, similar to BPD.…”

“…9,30-33 Although fetal and neonatal effects of IA inflammation/infection are wide-ranging. 9,12,[34][35][36][37] this review will specifically focus on the interaction between IA inflammation/ infection, and the fetal lungs and immune system.…”

Functional assessment of hyperoxia-induced lung injury after preterm birth in the rabbit

“…Many studies focus on the pathophysiology of BPD (1,17,18). In the postsurfactant era, human pathological specimens are less available since mortality of BPD has been reduced.…”