Complex roles of TGF-β signaling pathways in lung development and bronchopulmonary dysplasia

Abstract

As survival of extremely preterm infants continues to improve, there is also an associated increase in bronchopulmonary dysplasia (BPD), one of the most significant complications of preterm birth. BPD development is multifactorial resulting from exposure to multiple antenatal and postnatal stressors. BPD has both short-term health implications and long-term sequelae including increased respiratory, cardiovascular and neurological morbidity. Transforming growth factor beta (TGF-b) is an important signaling pathway in lung development, organ injury and fibrosis and is implicated in the development of BPD. This review provides a detailed account on the role of TGF-b in antenatal and postnatal lung development, the effect of known risk factors for BPD on the TGF-b signaling pathway, and how medications currently in use or under development, for the prevention or treatment of BPD, affect TGF-b signaling.

Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification

“…Of these pathways, we noted several predictions corresponding to TGFβ signaling, inhibitors of cell cycle, and Wnt signaling. These results are notable because TGFβ is a known driver of myofibroblast differentiation and profibrotic programs in fibroblasts 21,30 , while its overall contribution to alveolar simplification and BPD is unclear 5,52 . The prediction of increased cell cycle inhibition is also of interest because it suggests that the reduction of myofibroblasts in these models might be caused by their impaired proliferation.…”

“…Recent work has established an essential role for TGFβ signaling in normal alveolar development 52 , but the functional role of TGFβ in models of BPD and alveolar simplification remains unclear. Our scRNA-seq data showed increased TGFβ signaling in myofibroblasts in two injury models, so we hypothesized that excess TGFβ signaling might be a driver of disease pathogenesis.…”

“…Both IPA and NicheNet analyses predicted that TGFb signaling is activated in myofibroblasts in both models of alveolar simplification (Figures 3 and 4). Given the conflicting literature regarding the role of TGFb in normal lung development 5,18,52 , we sought to determine the functional significance of TGFb signaling during postnatal alveologenesis in both normoxic and hyperoxic conditions. We hypothesized that if excessive TGFb signaling is a pathologic response in hyperoxia, titration of a pan-TGFb-blocking antibody (1D11) could identify a therapeutic window to protect from disease while permitting normal development under normoxic conditions.…”

Endothelial deletion ofp53generates transitional endothelial cells and improves lung development during neonatal hyperoxia

“…Others, like Pgf -Vascular endothelial growth factor receptor 1 (Vegfr1), insulin-like growth factor 2 and IGF-1-receptor (Igf2 -Igf1r) and Angpt2 -Tek, have been associated with the regulation of angiogenesis (44,45). TGF-β, an important pathway in lung development that has been implicated in the pathogenesis of BPD and a p53-independent activator of p21 (39,46), was one of the shared interactions detected. Overall, this analysis indicates that non-EC contributions could influence vascular survival and repair upon hyperoxia.…”

Cadmium-induced Carcinogenesis in Respiratory Organs and the Prostate: Insights from Three Perspectives on Toxicogenomic Approach

“…Souchelnytskyi et al [ 23 ] demonstrated down-regulation of the SMAD protein phosphorylation as indication of abnormal transcription of its target genes. SMAD proteins are components of the TGF-β family signaling pathways [ 24 ], and dysfunction of TGF-β family signaling pathways causes bronchopulmonary diseases [ 25 ]. The suppression of ‘negative regulation of cellular response to growth factor stimulus’ can be interpreted as a healing effect.…”