Factor XII Deregulates Cell Communication and Contributes to Progression of Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by maladaptive remodelling of lung tissue associated with extracellular matrix deposition, abnormal re-epithelialization, and chronic inflammation. Although factor XII (FXII) has been linked to aforementioned process, its role in IPF is elusive. Here, we demonstrated elevated levels of FXII in lung tissue and bronchoalveolar lavage fluid in two independent cohorts of IPF patients. FXII immunoreactivity was mainly associated with mesenchymal cells and extracellular matrix in IPF lung tissue. Genetic ablation of f12 attenuated bleomycin-induced lung fibrosis in mice. Intratracheal application of FXII, but not its catalytically inactive mutant, reversed phenotype of f12-/- mice. Bleomycin-triggered lung fibrosis was not reduced in f11-/- and b1-/-b2-/- mice pointing towards direct cellular activities of activated FXII (FXIIa) driving lung fibrosis development. Exposure of FXIIa to human lung fibroblasts predominately affected pathways involved in cancer biology such as ErbB, MAPK, and VEGF signalling pathways. Inhibition of FXIIa using an anti-FXIIa antibody (3F7) attenuated lung fibrosis in animal models. Cumulatively, our data demonstrate profibrotic potential of FXIIa and open new avenues for therapeutic intervention in IPF patients.