Journal Article

Role of Protease-activated Receptor-2 in Idiopathic Pulmonary Fibrosis

Henneke, Ingrid, Markart, Philipp, Jablonska, Ewa, Zakrzewicz, Dariusz, Guenther, Andreas, Wygrecka, Malgorzata, Preissner, Klaus T., Kwapiszewska, Grazyna, Gerlach, Susanne von

2011

Overview

Abstract Rationale Activation of the coagulation cascade has been demonstrated in pulmonary fibrosis. In addition to its procoagulant function, various coagulation proteases exhibit cellular effects that may also contribute to fibrotic processes in the lung. Objective To investigate the importance of protease-activated receptor (PAR)-2 and its activators, coagulation factor VIIa (FVIIa)/tissue factor (TF), in the development of idiopathic pulmonary fibrosis (IPF). Methods Expression and localization of PAR-2 and its activators were examined in IPF lung tissue. The ability of PAR-2 to mediate various cellular processes was studied in vitro. Measurements and Main Results Expression of PAR-2 was strongly elevated in IPF lungs and was attributable to alveolar type II cells and fibroblasts/myofibroblasts. Transforming growth factor-β1, a key profibrotic cytokine, considerably enhanced PAR-2 expression in human lung fibroblasts. FVIIa stimulated proliferation of human lung fibroblasts and extracellular matrix production in a PAR-2–dependent manner, but did not initiate differentiation of fibroblasts into myofibroblasts. PAR-2/FVIIa-driven mitogenic activities were mediated via the p44/42 mitogen-activated protein kinase pathway and were independent of factor Xa and thrombin production. Proproliferative properties of FVIIa were markedly potentiated in the presence of TF and abrogated by TF antisense oligonucleotides. Hyperplastic alveolar type II cells overlying fibroblastic foci were found to be the source of FVII in IPF lungs. Moreover, TF colocalized with PAR-2 on fibroblasts/myofibroblasts in IPF lungs. Conclusions The PAR-2/TF/FVIIa axis may contribute to the development of pulmonary fibrosis; thus, interference with this pathway confers novel therapeutic potential for the treatment of IPF.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Biological and medical sciences / Cell Differentiation - physiology / Factor VIIa - physiology / Factor Xa - physiology / Female / Fibroblasts / Fibroblasts - pathology / Fibronectins - biosynthesis / Humans / Idiopathic Pulmonary Fibrosis - etiology / Idiopathic Pulmonary Fibrosis - metabolism / Idiopathic Pulmonary Fibrosis - pathology / In Vitro Techniques / Intensive care medicine / Kinases / Lung - pathology / Lungs / Male / Medical sciences / Middle Aged / Mitosis / Myofibroblasts - pathology / Osteopontin - biosynthesis / Pneumology / Pulmonary Alveoli - pathology / Pulmonary fibrosis / Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases / Receptor, PAR-2 - analysis / Receptor, PAR-2 - physiology / Thrombin - biosynthesis / Thromboplastin - physiology / Transforming Growth Factor beta - pharmacology