Background: Bronchopulmonary dysplasia (BPD) results from inhibition of alveolisation by mediators of injury. One mediator is transforming growth factor beta (TGFβ), which is a multifunctional signalling molecule. Signalling is initiated by binding of TGFβ to its receptors TBRI and TBRII, which activate SMAD and lead to altered expression of target genes. The level of bioactive TGFβ in the bronchoalveolar lavage fluid of preterm infants correlates with the severity of BPD. Therefore, reduction or inactivation of TGFβ and its signalling may present a potentially viable preventive strategy for BPD.
Objective: To investigate the mechanisms and the role of TGFβ in normal lung development and injury.
Methods: We used a Cre-LoxP system of conditional, cell type-specific gene deletion to inactivate either TBRI or TBRII genes in the murine lung. The Cre gene was directed by Nkx2.1 whose expression coincides with the onset of lung morphogenesis.
Results: Lung epithelial-specific deletion of the TBRI gene inhibited progenitor/stem cell lineages including those of Clara cells. Gene expression analysis showed abnormal Hes 1 and Mesh1 expression in TBRI (−/−) lungs, two pathways with important roles in progenitor/stem cell homeostasis. Epithelial-specific deletion of the TBRII gene resulted in precocious maturation, enhanced alveolisation and protection against lung injury (“super mice”).
Conclusions: The results demonstrate that the role of TGFβ in the lung is both physiological (“good”) and pathophysiological (“bad”) dependent on context. These data have implications for potential gene or other preventive/therapeutic strategies to abrogate TGFβ in the lungs of preterm neonates at risk of BPD.
Funding: This study was supported by NIH and The Hastings Foundation.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.