BIBF1120 inhibits fibroblasts proliferation and production of the extracellular matrix protein fibulin-1

Introduction: In patients with idiopathic pulmonary fibrosis (IPF) transforming growth factorbeta 1 (TGFβ1) induces excessive extracellular matrix (ECM) protein deposition leading to fibrosis. Our recent studies have shown that the glycoprotein fibulin-1 is increased in serum and lung tissue from patients with IPF and that their fibroblasts, which are the main fibrosis effector cells, produce more fibulin-1 than those from healthy people. Aim: To examine the modulation of fibroblast derived fibulin-1 from people with and without IPF. Methods: Primary parenchymal fibroblasts were derived from 5 patients with IPF and 5 without IPF (nonIPF). The production of fibulin-1 in the presence of cigarette smoke extract (CSE), foetal bovine serum (FBS) or TGFβ1 in the presence or absence of BIBF1120 (a triple kinase inhibitor the same as nintedanib) was measured by QPCR or ELISA. Proliferation was measured by MTT and CyQuant and cell attachment assessed by toluidine blue absorbance in fibroblasts from both groups. Results: CSE did not modulate fibulin-1 expression. Fibroblasts from IPF patients proliferated faster in 10% FBS and deposited more fibulin-1 in the presence of TGFβ1, compared to nonIPF fibroblasts, however attachment did not differ between the groups. BIBF1120 reduced proliferation and fibulin-1 deposition in the ECM, but did not influence attachment of fibroblasts. There were no differences in the degree of response to BIBF1120 between fibroblasts from patients with and without IPF. Conclusion: BIBF1120 inhibits fibroblastic behaviours that contribute to the pathogenesis of IPF. This new inhibitor may be effective in targeting the development of fibrosis in IPF patients