CFTR dysfunction increases endoglin and TGF‐ β signaling in airway epithelia

Endoglin ( ENG ) regulates signaling by transforming growth factor‐ β ( TGF ‐ β ), a genetic modifier of cystic fibrosis ( CF ) lung disease severity. We hypothesized that ENG mediates TGF ‐ β pathobiology in CF airway epithelia. Comparing CF and non‐ CF human lungs, we measured ENG by qPCR , immunoblotting and ELISA . In human bronchial epithelial cell lines (16 HBE ), we used CFTR si RNA knockdown and functional inhibition ( CFTR INH ‐172) to connect loss of CFTR to ENG synthesis. Plasmid overexpression of ENG assessed the direct effect of ENG on TGF ‐ β transcription and signal amplification in 16 HBE cells. We found ENG protein to be increased more than fivefold both in human CF bronchoalveolar fluid ( BALF ) and human CF lung homogenates. ENG transcripts were increased threefold in CF , with a twofold increase in TGF ‐ β signaling. CFTR knockdown in 16 HBE cells tripled ENG transcription and doubled protein levels with corresponding increases in TGF ‐ β signaling. Plasmid overexpression of ENG alone nearly doubled TGF ‐ β 1 mRNA and increased TGF ‐ β signaling in 16 HBE cells. These experiments identify that loss of CFTR function increases ENG expression in CF epithelia and amplifies TGF ‐ β signaling. Targeting ENG may offer a novel therapeutic opportunity to address TGF ‐ β associated pathobiology in CF .