Masterson, Joanne C. and Molloy, Emer L. and Gilbert, Jennifer L. and McCormack, Natasha and Adams, Aine and O'Dea, Shirley
Bone morphogenetic protein signalling in airway epithelial cells during regeneration.
Cellular Signalling, 23 (2).
Mechanisms of lung regeneration after injury remain poorly understood. Bone morphogenetic protein 4
(BMP4) is critical for lung morphogenesis and regulates differentiation of the airway epithelium during
development, although its mechanism of action is unknown. The role of BMPs in adult lungs is unclear. We
hypothesised that BMP signalling is involved in regeneration of damaged adult airways after injury. Our aims
were to characterise the regeneration process in 1-nitronaphthalene (1-NN) injured airways, to determine if
and when BMP signalling is activated during this process and investigate the effects of BMP4 on normal adult
airway epithelial cells (AECs). Rats were injected with 50 mg/kg 1-NN and protein expression in AECs was
examined by Western blotting of lung lysis lavage, and by immunofluorescence, at 6, 24, 48 and 96 h post
injection. Expression of signalling molecules p-ERK-1, p-ERK-2 and p-Smad1/5/8 in AECs peaked at 6 h post
injection, coincident with maximal inflammation and prior to airway denudation which occurred at 24 h.
While airways were re-epithelialised by 48 h, AEC proliferation peaked later at 96 h post 1-NN injection. In
vitro, BMP4 induced a mesenchymal-like morphology in normal AECs, downregulated E-cadherin expression
and increased migration in a wound closure assay. Thus, following acute injury, increased BMP signalling in
AECs coincides with inflammation and precedes airway denudation and re-epithelialisation. Our data indicate
that, similar to its role in controlling tissue architecture during development, BMP signalling regulates
regeneration of the airways following acute injury, involving downregulation of E-cadherin and induction of
migration in AECs
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