Background: Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that K Ca 3.1 K

Methods Using an in vitro wound repair model we explored the interaction of human Clara cells (H441 cell line) and type II AEC (A549 cell line). A transwell co-culture system was developed to determine the direct contact effect of densely populated Clara cells on wounded AEC monolayers. Results In serum-free media, lone H441 cell wound repair was higher than equivalent A549 cells, despite the fourfold slower doubling time of H441 cells. Serum-free conditioned media obtained from unwounded and wounded H441 monolayers did not show any significant influence on A549 wound repair. However, in a direct contact coculture A549-H441 cell model significant inhibition of A549 wound repair (p<0.005) was observed. Interestingly, H441 migration into the injured A549 layer was seen after 24 h; with a significant proportion of migrated H441 cells found at the wound margins. Coupled to this migration we observed a 50% reduction in A549 cell number at the wound margins. TUNEL assay detected about 40% A549 apoptosis in juxta-wound monolayers in A549-H441 direct contact (p<0.00001). This direct contact-induced apoptosis was significantly blocked by TRAIL-R1 and R2 combined receptor blockers (p<0.00001); whereas, Fas blocker failed to block this apoptosis. Conclusion In summary, direct contact of H441 cells induces apoptosis in the A549 monolayers through a TRAIL-dependent mechanism which disrupts wound margin integrity, inhibiting wound repair. This novel observation warrants further exploration of the role of Clara cell-alveolar epithelial cell interaction within the context of aberrant wound repair associated with chronic fibrotic lung disorders.