Pneumologie 2015; 69 - P05
DOI: 10.1055/s-0035-1551907

Coagulation factor XII mediates fibrotic response to lung injury

M Wygrecka 1, E Jablonska 1, I Henneke 4, T Renne 2, K Panousis 3, B McKenzie 3, D Kosanovic 4, G Kwapiszewska 5, MW Nolte 6, RT Schermuly 4, KT Preissner 1, P Markart 1
  • 1Department of Biochemistry, University of Gießen, Germany
  • 2Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden
  • 3CSL Limited, Victoria, Australia
  • 4Department of Internal Medicine, University of Gießen, Germany
  • 5Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
  • 6CSL Behring, Marburg, Germany

Rationale: Idiopathic pulmonary fibrosis (IPF) is the most aggressive and common form of diffuse parenchymal lung diseases. Albeit, disturbance in haemostatic balance was observed in IPF lungs, the role of factor XII (FXII) in the development of pulmonary fibrosis has never been addressed.

Methods: FXII expression was examined in the lungs of patients with IPF. The effects of FXII on fibroblast proliferation, differentiation and extracellular matrix production were assessed in vitro. The importance of FXII in experimental pulmonary fibrosis was examined using FXII knockout mice and FXII inhibitors.

Results: Increased expression and local activation of FXII in the lungs of IPF patients was observed. In fibrotic lungs, marked FXII immunoreactivity was associated with fibroblasts/myofibroblasts. Genetic ablation or pharmacological blockade of FXII amidolytic activity by corn trypsin inhibitor or infestin-4, abrogated fibrogenesis in a bleomycin lung injury model in mice. Whereas FXII procoagulant, complement-, and kinin-directed activities were dispensable for lung fibrogenesis, FXII mitogenic activities towards lung fibroblasts (LF) and its ability to induce LF differentiation and extracellular matrix production were decisive for this process. FXII-triggered profibrotic effects depended on its proteolytic activity and were mediated by u-PAR-α5β1 integrin complexes.

Conclusions: Our data demonstrate an unexpected coagulation-independent, profibrotic function of LF-produced FXII that provide new insights into the pathomechanism of IPF and may offer new treatment options.